Substituted 2-aza-bicyclo[2.2.2]octane-3-carboxylic acid (benzyl-cyano-methyl)-amides inhibitors of cathepsin C

ABSTRACT

This invention relates to 2-Aza-bicyclo[2.2.2]octane-3-carboxylic acid (benzyl-cyano-methyl)-amides of formula 1 
                         
and their use as inhibitors of Cathepsin C, pharmaceutical compositions containing the same, and methods of using the same as agents for treatment and/or prevention of diseases connected with dipeptidyl peptidase I activity, e.g. respiratory diseases.

FIELD OF INVENTION

This invention relates to 2-Aza-bicyclo[2.2.2]octane-3-carboxylic acid(benzyl-cyano-methyl)-amides of formula 1

and their use as inhibitors of Cathepsin C, pharmaceutical compositionscontaining the same, and methods of using the same as agents fortreatment and/or prevention of diseases connected with dipeptidylpeptidase I activity, e.g. respiratory diseases.

BACKGROUND INFORMATION

-   -   WO2004110988 discloses peptidyl nitrile inhibitors as        dipeptidyl-peptidase I (DPPI) inhibitors for the treatment of a        series of diseases.    -   WO2009074829 and WO2010142985 also disclose peptidyl nitrile        inhibitors as dipeptidyl-peptidase I (DPPI) inhibitors for the        treatment asthma, COPD or allergic rhinitis.

BRIEF SUMMARY OF THE INVENTION

Dipeptidyl-aminopeptidase I (DPPI or Cathepsin C; EC3.4.141), is alysosomal cysteine protease capable of removing dipeptides from theamino terminus of protein substrates. DPPI was first discovered byGutman and Fruton in 1948 (J. Biol. Chem. 174: 851-858, 1948). The cDNAof the human enzyme has been described in 1995 (Paris et al.; FEBS Lett369: 326-330, 1995). The DPPI protein is processed into a matureproteolytically active enzyme consisting of a heavy chain, a lightchain, and a propeptide that remains associated with the active enzyme(Wolters et al.; J. Biol. Chem. 273: 15514-15520, 1998). Whereas theother cysteine Cathepsins (e.g. B, H, K, L and S) are monomers, DPPI isa 200-kD tetramer with 4 identical subunits, each composed of the 3different polypeptide chains. DPPI is constitutively expressed in manytissues with highest levels in lung, kidney, liver and spleen (Kominamiet al.; Biol. Chem. Hoppe Seyler 373: 367-373, 1992). Consistent withits role in the activation of serine proteases from hematopoetic cells,DPPI is also relatively highly expressed in neutrophils, cytotoxiclymphocytes, natural killer cells, alveolar macrophages and mast cells.Recent data from DPPI deficient mice suggest that, besides being animportant enzyme in lysosomal protein degradation, DPPI also functionsas the key enzyme in the activation of granule serine proteases incytotoxic T lymphocytes and natural killer cells (granzymes A and B;Pham et al.; Proc. Nat. Acad. Sci. 96: 8627-8632, 1999), mast cells(chymase to and tryptase; Wolter et al.; J. Biol. Chem. 276:18551-18556, 2001), and neutrophils (Cathepsin G, elastase andproteinase 3; Adkison et al.; J. Clin. Invest. 109: 363.371, 2002). Onceactivated, these proteases are capable of degrading variousextracellular matrix components, which can lead to tissue damage andchronic inflammation.

Thus, inhibitors of Cathepsin C could potentially be useful therapeuticsfor the treatment of neutrophil-dominated inflammatory diseases such aschronic obstructive pulmonary disease (COPD), pulmonary emphysema,asthma, multiple sclerosis, and cystic fibrosis (Guay et al.; Curr.Topics Med. Chem. 10: 708-716, 2010; Laine and Busch-Petersen; ExpertOpin. Ther. Patents 20: 497-506, 2010). Rheumatoid arthritis is alsoanother chronic inflammatory disease where DPPI appears to play a role.Neutrophils are recruited to the site of joint inflammation and releaseCathepsin G, elastase and proteinase 3, proteases which are believed tobe responsible for cartilage destruction associated with rheumatoidarthritis. Indeed, DPPI deficient mice were protected against acutearthritis induced by passive transfer of monoclonal antibodies againsttype II collagen (Adkison et al.; J. Clin. Invest. 109: 363.371, 2002).

In light of the role DPPI plays in activating certain pro-inflammatoryserine proteases, it seems desirable to prepare compounds that inhibitits activity, which thereby inhibit downstream serine protease activity.It has been surprisingly found that the bicyclic compounds of thepresent invention possess potent Cathepsin C activity, high selectivityagainst other Cathepsins, e.g. Cathepsin K, and in general desirablepharmacokinetic properties.

DETAILED DESCRIPTION OF THE INVENTION

A compound of formula 1

wherein

-   R¹ is independently selected from among H, C₁₋₆-alkyl-, halogen,    HO—, C₁₋₆-alkyl-O—, H₂N—, C₁₋₆-alkyl-HN—, (C₁₋₆-alkyl)₂N— and    C₁₋₆-alkyl-C(O)HN—;-   or two R² are together C₁₋₄-alkylene;-   R² is selected from among    -   R^(2.1);    -   aryl-; optionally substituted with one, two or three residues        independently selected from R^(2.1); optionally substituted with        one R^(2.3);    -   C₅₀₋₁₀-heteroaryl-; containing one, two, three or four        heteroatoms independently selected from among S, S(O), S(O)₂, O        and N, wherein carbon atoms of the ring are optionally and        independently from each other substituted with one, two or three        R^(2.1); wherein nitrogen atoms of the ring are optionally and        independently from each other substituted with one, two or three        R^(2.2); wherein a carbon atom of the ring is optionally        substituted with one R^(2.3); a nitrogen atom of the ring is        optionally substituted with one R^(2.4); and    -   C₅₋₁₀-heterocyclyl-; containing one, two, three or four        heteroatoms independently selected from among S, S(O), S(O)₂, O        and N, wherein the ring is fully or partially saturated, wherein        carbon atoms of the ring are optionally and independently from        each other substituted with one, two or three or four R^(2.1);        wherein nitrogen atoms of the ring are optionally and        independently from each other substituted with one, two or three        R^(2.2); wherein a carbon atom of the ring is optionally        substituted with one R^(2.3) or one R^(2.5); a nitrogen atom of        the ring is optionally substituted with one R^(2.4) or    -   R² and R⁴ are together with two adjacent carbon atoms of the        phenyl ring a 5- or 6-membered aryl or heteroaryl, containing        one, two or three heteroatoms independently selected from among        S, S(O), S(O)₂, O and N, wherein carbon atoms of the ring are        optionally and independently from each other substituted with        one, two or three R^(2.1); wherein nitrogen atoms of the ring        are optionally and independently from each other substituted        with one, two or three R^(2.2);    -   R^(2.1) is independently selected from among H, halogen, NC—,        O═, HO—, H-A-, H-A-C₁₋₆-alkylene-, R^(2.1.1)-A-, C₁₋₆-alkyl-A-,        C₃₋₆-cycloalkyl-A-, C₁₋₆-haloalkyl-A-,        R^(2.1.1)—C₁₋₆-alkylene-A-, C₁₋₆-alkyl-A-C₁₋₆-alkylene-,        C₃₋₈-cycloalkyl-A-C₁₋₆-alkylene-,        C₁₋₆-haloalkyl-A-C₁₋₆-alkylene-,        R^(2.1.1)—C₁₋₆-alkylene-A-C₁₋₆-alkylene-,        R^(2.1.1)-A-C₁₋₆-alkylene-, HO—C₁₋₆-alkylene-A-,        HO—C₁₋₆-alkylene-A-C₁₋₆-alkylene-, C₁₋₆-alkyl-O—C₁₋₆-alkylene-A-        and C₁₋₆-alkyl-O—C₁₋₆-alkylene-A-C₁₋₆-alkylene-        -   R^(2.1.1) is independently selected from among            -   aryl-; optionally substituted independently from each                other with one, two or three R^(2.1.1.1);            -   C₅₋₁₀-heteroaryl-; containing one, two, three or four                heteroatoms independently selected from among S, S(O),                S(O)₂, O and N, wherein carbon atoms of the ring are                optionally and independently from each other substituted                with one, two or three R^(2.1.1.1); wherein nitrogen                atoms of the ring are optionally and independently from                each other substituted with one, two or three                R^(2.1.1.2); and            -   C₅₋₁₀-heterocyclyl-; containing one, two, three or four                heteroatoms independently selected from among S, S(O),                S(O)₂, O and N, wherein the ring is fully or partially                saturated, wherein carbon atoms of the ring are                optionally and independently from each other substituted                with one, two or three or four R^(2.1.1.1); wherein                nitrogen atoms of the ring are optionally and                independently from each other substituted with one, two                or three R^(2.1.1.2);            -   R^(2.1.1.1) is independently selected from among                halogen, HO—, O═, so C₁₋₆-alkyl-, C₁₋₆-alkyl-O—,                C₁₋₆-haloalkyl-, C₁₋₆-haloalkyl-O— and C₃₋₈-cycloalkyl-;            -   R^(2.1.1.2) is independently selected from among O═,                C₁₋₆-alkyl-, C₁₋₆-haloalkyl-; C₃₋₈-cycloalkyl-,                C₁₋₆-alkyl-O—C₁₋₆-alkyl-, H(O)C—, C₁₋₆-alkyl-(O)C—,                tetrahydrofuranylmethyl- and tetrahydropyranylmethyl-;    -   R^(2.2) is independently selected from among H-A-C₁₋₆-alkylene-,        C₃₋₈-cycloalkyl-, C₁₋₆-alkyl-A-C₁₋₆-alkylene-,        C₃₋₈-cycloalkyl-A-C₁₋₆-alkylene-,        C₁₋₆-haloalkyl-A-C₁₋₆-alkylene-, R^(2.1.1)-A-C₁₋₆-alkylene-,        C₁₋₆-alkyl-S(O)₂—, C₁₋₆-alkyl-C(O)— and R^(2.1)-A-;    -   R^(2.3) and R⁴ are together selected from    -   among —O—, —S—, —N(R^(2.3.1))—, —C(O)N(R^(2.3.1))—,        —N(R^(2.3.1))C(O)—, —S(O)₂N(R^(2.3.1))—, —N(R^(2.3.1))S(O)₂—,        —C(O)O—, —OC(O)—, —C(O)—, —S(O)—, —S(O)₂—, R^(2.3),    -   R^(2.3), —C(R^(2.3.2))═C(R^(2.3.2))—, —C═N—, —N═C—,        —C(R^(2.3.2))₂—O—, —O—C(R^(2.3.2))₂—,        —C(R^(2.3.2))₂N(R^(2.3.1))—, —N(R^(2.3.1))C(R^(2.3.2))₂— and        —C₁₋₄-alkylene-;        -   R^(2.3.1) is independently selected from among H,            C₁₋₆-alkyl-, C₁₋₆-haloalkyl-; C₃₋₈-cycloalkyl-,            HO—C₁₋₄-alkylene-, (C₁₋₄-alkyl)-O—C₁₋₄-alkylene-,            H₂N—C₁₋₄-alkylene-, (C₁₋₄-alkyl)HN—C₁₋₄-alkylene- and            (C₁₋₄-alkyl)₂N—C₁₋₄-alkylene-;        -   R^(2.3.2) is independently selected from among H,            C₁₋₆-alkyl-, C₁₋₆-haloalkyl-; C₃₋₈-cycloalkyl-,            HO—C₁₋₄-alkylene-, (C₁₋₄-alkyl)-O—C₁₋₄-alkylene-,            H₂N—C₁₋₄-alkylene-, (C₁₋₄-alkyl)HN—C₁₋₄-alkylene- and            (C₁₋₄-alkyl)₂N—C₁₋₄-alkylene-;    -   R^(2.4) and R⁴ are together selected from    -   among —N(R^(2.4.1))—, —C(O)N(R^(2.4.1))—, —N(R^(2.4.1))C(O)—,        —S(O)₂N(R^(2.4.1))—, —N(R^(2.4.1))S(O)₂—, —C(O)—, —S(O)—,        —S(O)₂—, —C(R^(2.4.2))═C(R^(2.4.2))—, —C═N—, —N═C—,        —C(R^(2.4.2))₂N(R^(2.4.1))—, —N(R^(2.4.1))C(R^(2.4.2))₂— and        —C₁₋₄-alkylene-; and        -   R^(2.4.1) is independently selected from among H,            C₁₋₆-alkyl-, C₁₋₆-haloalkyl-; C₃₋₈-cycloalkyl-,            HO—C₁₋₄-alkylene-, (C₁₋₄-alkyl)-O—C₁₋₄-alkylene-,            H₂N—C₁₋₄-alkylene-, (C₁₋₄-alkyl)HN—C₁₋₄-alkylene- and            (C₁₋₄-alkyl)₂N—C₁₋₄-alkylene-;        -   R^(2.4.2) is independently selected from among H,            C₁₋₆-alkyl-, C₁₋₆-haloalkyl-; C₃₋₈-cycloalkyl-,            HO—C₁₋₄-alkylene-, (C₁₋₄-alkyl)-O—C₁₋₄-alkylene-,            H₂N—C₁₋₄-alkylene-, (C₁₋₄-alkyl)HN—C₁₋₄-alkylene- and            (C₁₋₄-alkyl)₂N—C₁₋₄-alkylene-;    -   R^(2.5) and R⁴ are together selected from among —C(R^(2.5.1))═,        ═C(R^(2.5.1))— and —N═; and        -   R^(2.5.1) is independently selected from among H,            C₁₋₆-alkyl-, C₁₋₆-haloalkyl-; C₃₋₈-cycloalkyl-,            HO—C₁₋₄-alkylene-, (C₁₋₄-alkyl)-O—C₁₋₄-alkylene-,            H₂N—C₁₋₄-alkylene-, (C₁₋₄-alkyl)HN—C₁₋₄-alkylene- and            (C₁₋₄-alkyl)₂N—C₁₋₄-alkylene-;-   R³ is H or F;-   R⁴ is independently selected from among H, F, Cl, phenyl-H₂C—O—,    HO—, C₁₋₆-alkyl-, C₁₋₆-haloalkyl-, C₃₋₈-cycloalkyl-, C₁₋₆-alkyl-O—,    C₁₋₆-haloalkyl-O—, C₁₋₆-alkyl-HN—, (C₁₋₆-alkyl)₂-HN—,    C₁₋₆-alkyl-HN—C₁₋₄-alkylene-, (C₁₋₆-alkyl)₂-HN—C₁₋₄-alkylene-;    preferably F, Cl, phenyl-H₂C—O—, HO—, C₁₋₆-alkyl-, C₁₋₆-haloalkyl-,    C₃₋₈-cycloalkyl-, C₁₋₆-alkyl-O—, C₁₋₆-haloalkyl-O—, C₁₋₆-alkyl-HN—,    (C₁₋₆-alkyl)₂-HN—, C₁₋₆-alkyl-HN—C₁₋₄-alkylene- and    (C₁₋₆-alkyl)₂-HN—C₁₋₄-alkylene-;-   A is a bond or independently selected from among —O—, —S—, —N(R⁵)—,    —C(O)N(R⁵)—, —N(R⁵)C(O)—, —S(O)₂N(R⁵)—, —N(R⁵)S(O)₂—,    —S(O)(═NR⁵)—N(R⁵)—, —N(R⁵)(NR⁵═) S(O)—, —S(═NR⁵)₂—N(R⁵)—,    —N(R⁵)(NR⁵═)₂S—, —C(R⁵)═C(R⁵)—, —C≡C—, —C(O)O—, —OC(O)—, —C(O)—,    —S(O)—, —S(O)₂—, —S(═NR⁵)—, —S(O)(═NR⁵)—, —S(═NR⁵)₂—, —(R⁵)(O)S═N—,    —(R⁵N═)(O)S— and —N═(O)(R⁵)S—;-   R⁵ is independently selected from among H, C₁₋₆-alkyl- and NC—;    or a salt thereof.

Preferred Embodiments

Preferred are the above compounds of formula 1, wherein R¹ is R^(1.a)and R^(1.a) is independently selected from among H, C₁₋₄-alkyl-, F— andHO—.

Preferred are the above compounds of formula 1, wherein R¹ is R^(1.b)and R^(1.b) is H.

Preferred are the above compounds of formula 1, wherein R¹ is R^(1.c)and two R^(1.c) are together —CH₂—.

Preferred are the above compounds of formula 1, wherein R² is R^(2.a)and R^(2.a) is R^(2.1).

Preferred are the above compounds of formula 1, wherein R² is R^(2.b)and R^(2.b) is R^(2.1.a).

Preferred are the above compounds of formula 1, wherein R² is R^(2.c)and R^(2.c) is aryl-; optionally substituted with one, two or threeresidues independently selected from R^(2.1); optionally substitutedwith one R^(2.3).

Preferred are the above compounds of formula 1, wherein R² is R^(2.d)and R^(2.d) is phenyl; optionally substituted with one, two or threeresidues independently selected from R^(2.1); optionally substitutedwith one R^(2.3).

Preferred are the above compounds of formula 1, wherein R² is R^(2.e)and R^(2.e) is C_(5 or 6)-heteroaryl-, containing one, two, three orfour heteroatoms independently selected from among S, S(O), S(O)₂, O andN, wherein carbon atoms of the ring are optionally and independentlyfrom each other substituted with one, two or three R^(2.1); whereinnitrogen atoms of the ring are optionally and independently from eachother substituted with one, two or three R^(2.2); wherein a carbon atomof the ring is optionally substituted with one R^(2.3); a nitrogen atomof the ring is optionally substituted with one R^(2.4).

Preferred are the above compounds of formula 1, wherein R² is R^(2.f)and R^(2.f) is bicyclic C₇₋₁₀-heteroaryl-, each containing one, two,three or four heteroatoms independently selected from among S, S(O),S(O)₂, O and N, wherein carbon atoms of the ring are optionally andindependently from each other substituted with one, two or threeR^(2.1); wherein nitrogen atoms of the ring are optionally andindependently from each other substituted with one, two or threeR^(2.2); wherein a carbon atom of the ring is optionally substitutedwith one R^(2.3); a nitrogen atom of the ring is optionally substitutedwith one R^(2.4).

Preferred are the above compounds of formula 1, wherein R² is R^(2.g)and R^(2.g) is selected from among

wherein carbon atoms of the ring are optionally and independently fromeach other substituted with one, two or three R^(2.1); wherein possiblyavailable nitrogen atoms of the ring are optionally and independentlyfrom each other substituted with R^(2.2); wherein a carbon atom of thering is optionally substituted with one R^(2.3); a nitrogen atom of thering is optionally substituted with one R^(2.4)

Preferred are the above compounds of formula 1, wherein

R² is R^(2.g) and R^(2.g) is selected from among

wherein carbon atoms of the ring are optionally and independently fromeach other substituted with one, two or three R^(2.1); wherein possiblyavailable nitrogen atoms of the ring are optionally and independentlyfrom each other substituted with R^(2.2); and

-   R^(2.1) is R^(2.1.a) and R^(2.1.a) is selected from among H,    halogen, NC—, O═, HO—, H-A-, H-A-C₁₋₄-alkylene-, R^(2.1.1)-A-,    C₁₋₄-alkyl-A-, C₃₋₆-cycloalkyl-A-, C₁₋₄-haloalkyl-A-,    R^(2.1.1)—C₁₋₄-alkylene-A-, C₁₋₄-alkyl-A-C₁₋₄-alkylene-,    C₃₋₆-cycloalkyl-A-C₁₋₄-alkylene-, C₁₋₄-haloalkyl-A-C₁₋₄-alkylene-,    R^(2.1.1)—C₁₋₄-alkylene-A-C₁₋₄-alkylene-,    R^(2.1.1)-A-C₁₋₄-alkylene-, HO—C₁₋₄-alkylene-A-,    HO—C₁₋₄-alkylene-A-C₁₋₄-alkylene-, C₁₋₄-alkyl-O—C₁₋₄-alkylene-A- and    C₁₋₄-alkyl-O—C₁₋₄-alkylene-A-C₁₋₄-alkylene-; and    -   R^(2.1.1) is R^(2.1.1.a) and R^(2.1.1.a) is selected from among        -   aryl-, optionally substituted independently from each other            with one, two or three to residues independently selected            from R^(2.1.1.1);        -   C₅₋₁₀-heteroaryl-, containing one, two, three or four            heteroatoms selected independently from S, S(O), S(O)₂, O            and N, wherein carbon atoms of the ring are optionally and            independently from each other substituted with one, two or            three R^(2.1.1.1); wherein nitrogen atoms of the ring are            optionally and independently from each other substituted            with one, two or three R^(2.1.1.2);        -   C₅₋₁₀-heterocyclyl-, containing one, two, three or four            heteroatoms selected independently from S, S(O), S(O)₂, O            and N and the ring is fully or partially saturated, wherein            carbon atoms of the ring are optionally and independently            from each other substituted with one, two or three            R^(2.1.1.1); wherein nitrogen atoms of the ring are            optionally and independently from each other substituted            with one, two or three R^(2.1.1.2); and        -   R^(2.1.1.1) is independently selected from among halogen,            HO—, O═, C₁₋₄-alkyl-, C₁₋₄-alkyl-O—, C₁₋₄-haloalkyl- and            C₁₋₄-haloalkyl-O—, C₃₋₆-cycloalkyl-; and        -   R^(2.1.1.2) is independently selected from among O═,            C₁₋₄-alkyl-, C₁₋₄-haloalkyl-; C₃₋₆-cycloalkyl-,            C₁₋₄-alkyl-O—C₁₋₄-alkyl-, H(O)C—, C₁₋₄-alkyl-(O)C—,            tetrahydrofuranylmethyl- and tetrahydropyranylmethyl; and            R^(2.2) is R^(2.2.a) and R^(2.2.a) is independently selected            from among H-A-C₁₋₄-alkylene-, C₃₋₆-cycloalkyl-,            C₁₋₄-alkyl-A-C₁₋₄-alkylene-,            C₃₋₆-cycloalkyl-A-C₁₋₄-alkylene-,            C₁₋₄-haloalkyl-A-C₁₋₄-alkylene-, R^(2.1.1)-A-C₁₋₄-alkylene-,            C₁₋₄-alkyl-S(O)₂—, C₁₋₄-alkyl-C(O)— and R^(2.1.1)-A-.

Preferred are the above compounds of formula 1, wherein R² is R^(2.h)and R^(2.h) is selected from among pyrazole, thiophene- and furane,wherein carbon atoms of the ring are optionally and independently fromeach other substituted with one, two or three R^(2.1); wherein possiblyavailable nitrogen atoms of the ring are optionally and independentlyfrom each other substituted with R^(2.2); wherein a carbon atom of thering is optionally substituted with one R^(2.3); a nitrogen atom of thering is optionally substituted with one R^(2.4).

Preferred are the above compounds of formula 1, wherein R² is R^(2.i)and R^(2.i) is selected from among C₆₋heterocyclyl- andC₇₋₁₀-heterocyclyl-, each containing one, two, three or four heteroatomsindependently selected from among S, O and N and the ring is fully orpartially saturated, wherein carbon atoms of the ring are optionally andindependently from each other substituted with one, two or threeR^(2.1); wherein nitrogen atoms of the ring are optionally andindependently from each other substituted with one, two or threeR^(2.2); wherein a carbon atom of the ring is optionally substitutedwith one R^(2.3) or one R^(2.5); a nitrogen atom of the ring isoptionally substituted with one R^(2.4).

Preferred are the above compounds of formula 1, wherein R² is R^(2.j)and R^(2.j) is selected from among

wherein carbon atoms of the ring are optionally and independently fromeach other substituted with one, two or three R^(2.1); wherein possiblyavailable nitrogen atoms of the ring are optionally and independentlyfrom each other substituted with R^(2.2); wherein a carbon atom of thering is optionally substituted with one R^(2.3) or one R^(2.5); anitrogen atom of the ring is optionally substituted with one R^(2.4).

Preferred are the above compounds of formula 1, wherein

R² is R^(2.j) and R^(2.j) is selected from among

wherein carbon atoms of the ring are optionally and independently fromeach other substituted with one, two or three R^(2.1); wherein possiblyavailable nitrogen atoms of the ring are optionally and independentlyfrom each other substituted with R^(2.2); and

-   R^(2.1) is R^(2.1.a) and R^(2.1.a) is selected from among H,    halogen, NC—, O═, HO—, H-A-, H-A-C₁₋₄-alkylene-, R^(2.1.1)-A-,    C₁₋₄-alkyl-A-, C₃₋₆-cycloalkyl-A-, C₁₋₄-haloalkyl-A-,    R^(2.1.1)—C₁₋₄-alkylene-A-, C₁₋₄-alkyl-A-C₁₋₄-alkylene-,    C₃₋₆-cycloalkyl-A-C₁₋₄-alkylene-, C₁₋₄-haloalkyl-A-C₁₋₄-alkylene-,    R^(2.1.1)—C₁₋₄-alkylene-A-C₁₋₄-alkylene-,    R^(2.1.1)-A-C₁₋₄-alkylene-, HO—C₁₋₄-alkylene-A-,    HO—C₁₋₄-alkylene-A-C₁₋₄-alkylene-, C₁₋₄-alkyl-O—C₁₋₄-alkylene-A- and    C₁₋₄-alkyl-O—C₁₋₄-alkylene-A-C₁₋₄-alkylene-; and    -   R^(2.1.1) is R^(2.1.1.a) and R^(2.1.1.a) is selected from among        -   aryl-, optionally substituted independently from each other            with one, two or three residues independently selected from            R^(2.1.1.1);        -   C₅₋₁₀-heteroaryl-, containing one, two, three or four            heteroatoms selected independently from S, S(O), S(O)₂, O            and N, wherein carbon atoms of the ring are optionally and            independently from each other substituted with one, two or            three R^(2.1.1.1); wherein nitrogen atoms of the ring are            optionally and independently from each other substituted            with one, two or three R^(2.1.1.2); and        -   C₅₋₁₀-heterocyclyl-, containing one, two, three or four            heteroatoms selected independently from S, S(O), S(O)₂, O            and N and the ring is fully or partially saturated, wherein            carbon atoms of the ring are optionally and independently            from each other substituted with one, two or three            R^(2.1.1.1); wherein nitrogen atoms of the ring are            optionally and independently from each other substituted            with one, two or three R^(2.1.1.2); and    -   R^(2.1.1.1) is independently selected from among halogen, HO—,        O═, C₁₋₄-alkyl-, C₁₋₄-alkyl-O—, C₁₋₄-haloalkyl-,        C₁₋₄-haloalkyl-O— and C₃₋₆-cycloalkyl-; and    -   R^(2.1.1.2) is independently selected from among O═,        C₁₋₄-alkyl-, C₁₋₄-haloalkyl-; C₃₋₆-cycloalkyl-,        C₁₋₄-alkyl-O—C₁₋₄-alkyl-, H(O)C—, C₁₋₄-alkyl-(O)C—,        tetrahydrofuranylmethyl- and tetrahydropyranylmethyl; and        R^(2.2) is R^(2.2.a) and R^(2.2.a) is independently selected        from among H-A-C₁₋₄-alkylene-, C₃₋₆-cycloalkyl-,        C₁₋₄-alkyl-A-C₁₋₄-alkylene-, C₃₋₆-cycloalkyl-A-C₁₋₄-alkylene-,        C₁₋₄-haloalkyl-A-C₁₋₄-alkylene-, R^(2.1.1)-A-C₁₋₄-alkylene-,        C₁₋₄-alkyl-S(O)₂—, C₁₋₄-alkyl-C(O)— and R^(2.1.1)-A-.

Preferred are the above compounds of formula 1, wherein R² is R^(2.k)and R^(2.k) is selected from among

wherein carbon atoms of the ring are optionally and independently fromeach other substituted with one, two or three R^(2.1); wherein possiblyavailable nitrogen atoms of the ring are optionally and independentlyfrom each other substituted with R^(2.2); wherein a carbon atom of thering is optionally substituted with one R^(2.3) or one R^(2.5); anitrogen atom of the ring is optionally substituted with one R^(2.4).

Preferred are the above compounds of formula 1, wherein R² is R^(2.1)and R^(2.1) is selected from among

wherein carbon atoms of the ring are optionally and independently fromeach other substituted with one, two, three or four R^(2.1); whereinpossibly available nitrogen atoms of the ring are optionally andindependently from each other substituted with R^(2.2); wherein a carbonatom of the ring is optionally substituted with one R^(2.3) or oneR^(2.5); a nitrogen atom of the ring is optionally substituted with oneR^(2.4).

Preferred are the above compounds of formula 1, wherein R² is R^(2.m)and R^(2.m) is together with R⁴ and two adjacent carbon atoms of thephenyl ring a 5- or 6-membered aryl or heteroaryl, containing one, twoor three heteroatoms independently selected from among S, S(O), S(O)₂, Oand N, preferably pyrazole- and naphtene, wherein carbon atoms of thering are optionally and independently from each other substituted withone, two or three R^(2.1), wherein possibly available nitrogen atoms ofthe ring are optionally and independently from each other substitutedwith one, two or three R^(2.2).

Preferred are the above compounds of formula 1, wherein

R² is R^(2.m) and R^(2.m) is together with R⁴ and two adjacent carbonatoms of the phenyl ring a 5- or 6-membered aryl or heteroaryl,containing one, two or three heteroatoms independently selected is fromamong S, S(O), S(O)₂, O and N, wherein carbon atoms of the ring areoptionally and independently from each other substituted with one, twoor three R^(2.1), wherein possibly available nitrogen atoms of the ringare optionally and independently from each other substituted with one,two or three R^(2.2); and

-   R^(2.1) is R^(2.1.a) and R^(2.1.a) is selected from among H,    halogen, NC—, O═, HO—, H-A-, H-A-C₁₋₄-alkylene-, R^(2.1.1)-A-,    C₁₋₄-alkyl-A-, C₃₋₆-cycloalkyl-A-, C₁₋₄-haloalkyl-A-,    R^(2.1.1)—C₁₋₄-alkylene-A-, C₁₋₄-alkyl-A-C₁₋₄-alkylene-,    C₃₋₆-cycloalkyl-A-C₁₋₄-alkylene-, C₁₋₄-haloalkyl-A-C₁₋₄-alkylene-,    R^(2.1.1)—C₁₋₄-alkylene-A-C₁₋₄-alkylene-,    R^(2.1.1)-A-C₁₋₄-alkylene-, HO—C₁₋₄-alkylene-A-,    HO—C₁₋₄-alkylene-A-C₁₋₄-alkylene-, C₁₋₄-alkyl-O—C₁₋₄-alkylene-A- and    C₁₋₄-alkyl-O—C₁₋₄-alkylene-A-C₁₋₄-alkylene-; and    -   R^(2.1.1) is R^(2.1.1.a) and R^(2.1.1.a) is selected from among        -   aryl-, optionally substituted independently from each other            with one, two or three residues independently selected from            R^(2.1.1.1);        -   C₅₋₁₀-heteroaryl-, containing one, two, three or four            heteroatoms selected independently from S, S(O), S(O)₂, O            and N, wherein carbon atoms of the ring are optionally and            independently from each other substituted with one, two or            three R^(2.1.1.1); wherein nitrogen atoms of the ring are            optionally and independently from each other substituted            with one, two or three R^(2.1.1.2); and        -   C₅₋₁₀-heterocyclyl-, containing one, two, three or four            heteroatoms selected independently from S, S(O), S(O)₂, O            and N and the ring is fully or partially saturated, wherein            carbon atoms of the ring are optionally and independently            from each other substituted with one, two or three            R^(2.1.1.1); wherein nitrogen atoms of the ring are            optionally and independently from each other substituted            with one, two or three R^(2.1.1.2); and    -   R^(2.1.1.1) is independently selected from among halogen, HO—,        O═, C₁₋₄-alkyl-, C₁₋₄-alkyl-O—, C₁₋₄-haloalkyl-,        C₁₋₄-haloalkyl-O— and C₃₋₆-cycloalkyl-; and    -   R^(2.1.1.2) is independently selected from among O═,        C₁₋₄-alkyl-, C₁₋₄-haloalkyl-; C₃₋₆-cycloalkyl-,        C₁₋₄-alkyl-O—C₁₋₄-alkyl-, H(O)C—, C₁₋₄-alkyl-(O)C—,        tetrahydrofuranylmethyl- and tetrahydropyranylmethyl; and        R^(2.2) is R^(2.2.a) and R^(2.2.a) is independently selected        from among H-A-C₁₋₄-alkylene-, C₃₋₆-cycloalkyl-,        C₁₋₄-alkyl-A-C₁₋₄-alkylene-, C₃₋₆-cycloalkyl-A-C₁₋₄-alkylene-,        C₁₋₄-haloalkyl-A-C₁₋₄-alkylene-, R^(2.1.1)-A-C₁₋₄-alkylene-,        C₁₋₄-alkyl-S(O)₂—, C₁₋₄-alkyl-C(O)— and R^(2.1.1)-A-.

Preferred are the above compounds of formula 1, wherein R² is R^(2.n)and R^(2.n) is selected from among aryl-, pyrazole, thiophene- andfurane; wherein carbon atoms of the ring are optionally andindependently from each other substituted with one, two, three or fourR^(2.1); wherein possibly available nitrogen atoms of the ring areoptionally and independently from each other substituted with R^(2.2);wherein a carbon atom of the ring is optionally substituted with oneR^(2.3); a nitrogen atom of the ring is optionally substituted with oneR^(2.4); or R^(2.n) is selected from among

wherein carbon atoms of the ring are optionally and independently fromeach other substituted with one, two, three or four R^(2.1); whereinpossibly available nitrogen atoms of the ring are optionally andindependently from each other substituted with R^(2.2); wherein a carbonatom of the ring is optionally substituted with one R^(2.3) or oneR^(2.5); a nitrogen atom of the ring is optionally substituted with oneR^(2.4).

Preferred are the above compounds of formula 1, wherein

R² is R^(2.n) and R^(2.n) is selected from among aryl-, pyrazole,thiophene- and furane; wherein carbon atoms of the ring are optionallyand independently from each other substituted with one, two, three orfour R^(2.1); wherein possibly available nitrogen atoms of the ring areoptionally and independently from each other substituted with R^(2.2);wherein a carbon atom of the ring is optionally substituted with oneR^(2.3); a nitrogen atom of the ring is optionally substituted with oneR^(2.4); or R^(2.n) is selected from among

wherein carbon atoms of the ring are optionally and independently fromeach other substituted with one, two, three or four R^(2.1); whereinpossibly available nitrogen atoms of the ring are optionally andindependently from each other substituted with R^(2.2); wherein a carbonatom of the ring is optionally substituted with one R^(2.3) or oneR^(2.5); a nitrogen atom of the ring is optionally substituted with oneR^(2.4); and

-   R^(2.1) is R^(2.1.a) and R^(2.1.a) is selected from among H,    halogen, NC—, O═, HO—, H-A-, H-A-C₁₋₄-alkylene-, R^(2.1.1)-A-,    C₁₋₄-alkyl-A-, C₃₋₆-cycloalkyl-A-, C₁₋₄-haloalkyl-A-,    R^(2.1.1)—C₁₋₄-alkylene-A-, C₁₋₄-alkyl-A-C₁₋₄-alkylene-,    C₃₋₆-cycloalkyl-A-C₁₋₄-alkylene-, C₁₋₄-haloalkyl-A-C₁₋₄-alkylene-,    R^(2.1.1)—C₁₋₄-alkylene-A-C₁₋₄-alkylene-,    R^(2.1.1)-A-C₁₋₄-alkylene-, HO—C₁₋₄-alkylene-A-,    HO—C₁₋₄-alkylene-A-C₁₋₄-alkylene-, C₁₋₄-alkyl-O—C₁₋₄-alkylene-A— and    C₁₋₄-alkyl-O—C₁₋₄-alkylene-A-C₁₋₄-alkylene-; and    -   R^(2.1.1) is R^(2.1.1.a) and R^(2.1.1.a) is selected from among        -   aryl-, optionally substituted independently from each other            with one, two or three residues independently selected from            R^(2.1.1.1);        -   C₅₋₁₀-heteroaryl-, containing one, two, three or four            heteroatoms selected independently from S, S(O), S(O)₂, O            and N, wherein carbon atoms of the ring are optionally and            independently from each other substituted with one, two or            three R^(2.1.1.1); wherein nitrogen atoms of the ring are            optionally and independently from each other substituted            with one, two or three R^(2.1.1.2); and        -   C₅₋₁₀-heterocyclyl-, containing one, two, three or four            heteroatoms selected independently from S, S(O), S(O)₂, O            and N and the ring is fully or partially saturated, wherein            carbon atoms of the ring are optionally and independently            from each other substituted with one, two or three            R^(2.1.1.1); wherein nitrogen atoms of the ring are            optionally and independently from each other substituted            with one, two or three R^(2.1.1.2); and    -   R^(2.1.1.1) is independently selected from among halogen, HO—,        O═, C₁₋₄-alkyl-, C₁₋₄-alkyl-O—, C₁₋₄-haloalkyl-,        C₁₋₄-haloalkyl-O—, C₃₋₆-cycloalkyl-; and    -   R^(2.1.1.2) is independently selected from among O═,        C₁₋₄-alkyl-, C₁₋₄-haloalkyl-; C₃₋₆-cycloalkyl-,        C₁₋₄-alkyl-O—C₁₋₄-alkyl-, H(O)C—, C₁₋₄-alkyl-(O)C—,        tetrahydrofuranylmethyl- and tetrahydropyranylmethyl; and-   R^(2.2) is R^(2.2.a) and R^(2.2.a) is independently selected from    among H-A-C₁₋₄-alkylene-, C₃₋₆-cycloalkyl-,    C₁₋₄-alkyl-A-C₁₋₄-alkylene-, C₃₋₆-cycloalkyl-A-C₁₋₄-alkylene-,    C₁₋₄-haloalkyl-A-C₁₋₄-alkylene-, R^(2.1)-A-C₁₋₄-alkylene-,    C₁₋₄-alkyl-S(O)₂— and C₁₋₄-alkyl-C(O)—, R^(2.1.1)-A-; and-   R^(2.3) is together with R⁴ a group R^(2.3.a) and R^(2.3.a) is    selected from    -   among —O—, —S—, —N(R^(2.3.1))—, —C(O)N(R^(2.3.1))—,        —N(R^(2.3.1))C(O)—, —S(O)₂N(R^(2.3.1))—, —N(R^(2.3.1))S(O)₂—,        —C(O)O—, —OC(O)—, —C(O)—, —S(O)—, —S(O)₂—,        —C(R^(2.3.2))═C(R^(2.3.2))—, —C═N—, —N═C—, —C(R^(2.3.2))₂—O—,        —O—C(R^(2.3.2))₂₋, —C(R^(2.3.2))₂N(R^(2.3.1))—,        —N(R^(2.3.1))C(R^(2.3.2))₂— and —C₁₋₄-alkylene-; and        -   R^(2.3.1) is independently selected from among H,            C₁₋₄-alkyl-, C₁₋₄-haloalkyl-, C₃₋₆-cycloalkyl-,            HO—C₁₋₄-alkylene-, (C₁₋₄-alkyl)-O—C₁₋₄-alkylene-,            H₂N—C₁₋₄-alkylene-, (C₁₋₄-alkyl)HN—C₁₋₄-alkylene- and            (C₁₋₄-alkyl)₂N—C₁₋₄-alkylene-;        -   R^(2.3.2) is independently selected from among H,            C₁₋₄-alkyl-, C₁₋₄-haloalkyl-, C₃₋₆-cycloalkyl-,            HO—C₁₋₄-alkylene-, (C₁₋₄-alkyl)-O—C₁₋₄-alkylene-,            H₂N—C₁₋₄-alkylene-, (C₁₋₄-alkyl)HN—C₁₋₄-alkylene- and            (C₁₋₄-alkyl)₂N—C₁₋₄-alkylene-; and-   R^(2.4) is together with R⁴ a group R^(2.4.a) and R^(2.4.a) is    selected from    -   among —N(R^(2.4.1))—, —C(O)N(R^(2.4.1))—, —N(R^(2.4.1))C(O)—,        —S(O)₂N(R^(2.4.1))—, —N(R^(2.4.1))S(O)₂—, —C(O)—, —S(O)—,        —S(O)₂—, —C(R^(2.4.2))═C(R^(2.4.2))—, —C═N—, —N═C—,        —C(R^(2.4.2))₂N(R^(2.4.1))—, —N(R^(2.4.1))C(R^(2.4.2))₂- and        —C₁₋₄-alkylene-; and    -   R^(2.4.1) is independently selected from among H, C₁₋₄-alkyl-,        C₁₋₄-haloalkyl-, C₃₋₆-cycloalkyl-, HO—C₁₋₄-alkylene- and        (C₁₋₄-alkyl)-O—C₁₋₄-alkylene-, H₂N—C₁₋₄-alkylene-,        (C₁₋₄-alkyl)HN—C₁₋₄-alkylene-, (C₁₋₄-alkyl)₂N—C₁₋₄-alkylene-;    -   R^(2.4.2) is independently selected from among H, C₁₋₄-alkyl-,        C₁₋₄-haloalkyl-, C₃₋₆-cycloalkyl-, HO—C₁₋₄-alkylene-,        (C₁₋₄-alkyl)-O—C₁₋₄-alkylene-, H₂N—C₁₋₄-alkylene-,        (C₁₋₄-alkyl)HN—C₁₋₄-alkylene- and (C₁₋₄-alkyl)₂N—C₁₋₄-alkylene-;        and        R^(2.5) is together with R⁴ a group R^(2.5.a) and R^(2.5.a) is        selected from among —C(R^(2.5.1))=, ═C(R^(2.5.1))— and —N═; and    -   R^(2.5.1) is independently selected from among H, C₁₋₄-alkyl-,        C₁₋₄-haloalkyl-, C₃₋₆-cycloalkyl-, HO—C₁₋₄-alkylene-,        (C₁₋₄-alkyl)-O—C₁₋₄-alkylene-, H₂N—C₁₋₄-alkylene-,        (C₁₋₄-alkyl)HN—C₁₋₄-alkylene- and (C₁₋₄-alkyl)₂N—C₁₋₄-alkylene-.

Preferred are the above compounds of formula 1, wherein R² is R^(2.o)and R^(2.o) is selected from among aryl-, pyrazole, thiophene- andfurane; wherein carbon atoms of the ring are optionally andindependently from each other substituted with one, two, three or fourR^(2.1); wherein possibly available nitrogen atoms of the ring areoptionally and independently from each other substituted with R^(2.2);wherein a carbon atom of the ring is optionally substituted with oneR^(2.3); a nitrogen atom of the ring is optionally substituted with oneR^(2.4).

Preferred are the above compounds of formula 1, wherein R² is R^(2.p)and R^(2.p) is selected from among

wherein carbon atoms of the ring are optionally and independently fromeach other substituted with one, two, three or four R^(2.1); whereinpossibly available nitrogen atoms of the ring are optionally andindependently from each other substituted with R^(2.2); wherein a carbonatom of the ring is optionally substituted with one R^(2.3) or oneR^(2.5); a nitrogen atom of the ring is optionally substituted with oneR^(2.4).

Preferred are the above compounds of formula 1, wherein R^(2.1) isR^(2.1.a) and R^(2.1.a) is selected from among H, halogen, NC—, O═, HO—,H-A-, H-A-C₁₋₄-alkylene-, R^(2.1.1)-A-, C₁₋₄-alkyl-A-,C₃₋₆-cycloalkyl-A-, C₁₋₄-haloalkyl-A-, R^(2.1.1)—C₁₋₄-alkylene-A-,C₁₋₄-alkyl-A-C₁₋₄-alkylene-, C₃₋₆-cycloalkyl-A-C₁₋₄-alkylene-,C₁₋₄-haloalkyl-A-C₁₋₄-alkylene-,R^(2.1.1)—C₁₋₄-alkylene-A-C₁₋₄-alkylene-, R^(2.1.1)-A-C₁₋₄-alkylene-,HO—C₁₋₄-alkylene-A-, HO—C₁₋₄-alkylene-A-C₁₋₄-alkylene-,C₁₋₄-alkyl-O—C₁₋₄-alkylene-A- andC₁₋₄-alkyl-O—C₁₋₄-alkylene-A-C₁₋₄-alkylene-.

Preferred are the above compounds of formula 1, wherein R^(2.1.1) isR^(2.1.1.a) and R^(2.1.1.a) is selected from among

-   -   aryl-, optionally substituted independently from each other with        one, two or three residues independently selected from        R^(2.1.1.1);    -   C₅₋₁₀-heteroaryl-, containing one, two, three or four        heteroatoms selected independently from S, S(O), S(O)₂, O and N,        wherein carbon atoms of the ring are optionally and        independently from each other substituted with one, two or three        R^(2.1.1.1); wherein nitrogen atoms of the ring are optionally        and independently from each other substituted with one, two or        three R^(2.1.1.2); and    -   C₅₋₁₀-heterocyclyl-, containing one, two, three or four        heteroatoms selected independently from S, S(O), S(O)₂, O and N        and the ring is fully or partially saturated, wherein carbon        atoms of the ring are optionally and independently from each        other substituted with one, two or three R^(2.1.1.1); wherein        nitrogen atoms of the ring are optionally and independently from        each other substituted with one, two or three R^(2.1.1.2); and

-   R^(2.1.1.1) is independently selected from among halogen, HO—, O═,    C₁₋₄-alkyl-, C₁₋₄-alkyl-O—, C₁₋₄-haloalkyl- and C₁₋₄-haloalkyl-O—,    C₃₋₆-cycloalkyl-; and

-   R^(2.1.1.2) is independently selected from among O═, C₁₋₄-alkyl-,    C₁₋₄-haloalkyl-; C₃₋₆-cycloalkyl-, C₁₋₄-alkyl-O—C₁₋₄-alkyl-, H(O)C—,    C₁₋₄-alkyl-(O)C—, tetrahydrofuranylmethyl- and    tetrahydropyranylmethyl.

Preferred are the above compounds of formula 1, wherein R^(2.1.1) isR^(2.1.1.b) and R^(2.1.1.b) is phenyl or selected from among

wherein carbon atoms of the ring are optionally and independently fromeach other substituted with one, two or three R^(2.1.1.1), whereinpossibly available nitrogen atoms of the ring are optionally andindependently from each other substituted with R^(2.1.1.2); and

-   R^(2.1.1.1) is independently selected from among halogen, HO—, O═,    C₁₋₄-alkyl-, C₁₋₄-alkyl-O—, C₁₋₄-haloalkyl- and C₁₋₄-haloalkyl-O—,    C₃₋₆-cycloalkyl-; and-   R^(2.1.1.2) is independently selected from among O═, C₁₋₄-alkyl-,    C₁₋₄-haloalkyl-; C₃₋₆-cycloalkyl-, C₁₋₄-alkyl-O—C₁₋₄-alkyl-, H(O)C—,    C₁₋₄-alkyl-(O)C—, tetrahydrofuranylmethyl- and    tetrahydropyranylmethyl.

Preferred are the above compounds of formula 1, wherein R^(2.1.1) isR^(2.1.1.c) and R^(2.1.1.c) is phenyl or selected from among

wherein carbon atoms of the ring are optionally and independently fromeach other substituted with one, two or three R^(2.1.1.1), whereinpossibly available nitrogen atoms of the ring are optionally andindependently from each other substituted with R^(2.1.1.2); and

-   R^(2.1.1.1) is independently selected from among F, Cl, Me, MeO— and    cyclopropyl-; and-   R^(2.1.1.2) is independently selected from among Me,    tetrahydrofuranylmethyl- and tetrahydropyranylmethyl.

Preferred are the above compounds of formula 1, wherein R^(2.1.2) isR^(2.1.2.a) and R^(2.1.2.a) is selected from among H, NC—, C₁₋₄-alkyl-,C₁₋₄-haloalkyl-, C₃₋₆-cycloalkyl-, HO—C₁₋₄-alkylene- and(C₁₋₄-alkyl)-O—C₁₋₄-alkylene-.

Preferred are the above compounds of formula 1, wherein R^(2.1.2) isR^(2.1.2.b) and R^(2.1.2.b) is selected from among H, C₁₋₄-alkyl- andC₃₋₆-cycloalkyl-;

Preferred are the above compounds of formula 1, wherein R^(2.2) isR^(2.2.a) and R^(2.2.a) is independently selected from amongH-A-C₁₋₄-alkylene-, C₃₋₆-cycloalkyl-, C₁₋₄-alkyl-A-C₁₋₄-alkylene-,C₃₋₆-cycloalkyl-A-C₁₋₄-alkylene-, C₁₋₄-haloalkyl-A-C₁₋₄-alkylene-,R^(2.1.1)-A-C₁₋₄-alkylene-, C₁₋₄-alkyl-S(O)₂—, C₁₋₄-alkyl-C(O)— andR^(2.1.1)-A-;

Preferred are the above compounds of formula 1, wherein R^(2.2) isR^(2.2.b) and R^(2.2.b) is together with R⁴ selected from among —C(O)—,—S(O)—, —S(O)₂—, —C(R^(2.1.2))═C(R^(2.1.2))— and —C₁₋₄-alkylene-;

Preferred are the above compounds of formula 1, wherein R^(2.3) istogether with R⁴ a group R^(2.3.a) and R^(2.3.a) is selected from

among —O—, —S—, —N(R^(2.3.1))—, —C(O)N(R^(2.3.1))—, —N(R^(2.3.1))C(O)—,—S(O)₂N(R^(2.3.1))—, —N(R^(2.3.1))S(O)₂—, —C(O)O—, —OC(O)—, —C(O)—,—S(O)—, —S(O)₂—, —C(R^(2.3.2))═C(R^(2.3.2))—, —C═N—, —N═C—,—C(R^(2.3.2))₂—O—, —O—C(R^(2.3.2))₂—, —C(R^(2.3.2))₂N(R^(2.3.1))—,—N(R^(2.3.1))C(R^(2.3.2))₂— and —C₁₋₄-alkylene-; and

-   R^(2.3.1) is independently selected from among H, C₁₋₄-alkyl-,    C₁₋₄-haloalkyl-, C₃₋₆-cycloalkyl-, HO—C₁₋₄-alkylene-,    (C₁₋₄-alkyl)-O—C₁₋₄-alkylene-, H₂N—C₁₋₄-alkylene-,    (C₁₋₄-alkyl)HN—C₁₋₄-alkylene- and (C₁₋₄-alkyl)₂N—C₁₋₄-alkylene-;-   R^(2.3.2) is independently selected from among H, C₁₋₄-alkyl-,    C₁₋₄-haloalkyl-, C₃₋₆-cycloalkyl-, HO—C₁₋₄-alkylene-,    (C₁₋₄-alkyl)-O—C₁₋₄-alkylene-, H₂N—C₁₋₄-alkylene-,    (C₁₋₄-alkyl)HN—C₁₋₄-alkylene- and (C₁₋₄-alkyl)₂N—C₁₋₄-alkylene-.

Preferred are the above compounds of formula 1, wherein R^(2.4) istogether with R⁴ a group R^(2.4.a) and R^(2.4.a) is selected from

among —N(R^(2.4.1))—, —C(O)N(R^(2.4.1))—, —N(R^(2.4.1))C(O)—,—S(O)₂N(R^(2.4.1))—, —N(R^(2.4.1))S(O)₂—, —C(O)—, —S(O)—, —S(O)₂—,—C(R^(2.4.2))═C(R^(2.4.2))—, —C═N—, —N═C—, —C(R^(2.4.2))₂N(R^(2.4.1))—,—N(R^(2.4.1))C(R^(2.4.2))₂— and —C₁₋₄-alkylene-; and

-   R^(2.4.1) is independently selected from among H, C₁₋₄-alkyl-,    C₁₋₄-haloalkyl-, C₃₋₆-cycloalkyl-, HO—C₁₋₄-alkylene-,    (C₁₋₄-alkyl)-O—C₁₋₄-alkylene-, H₂N—C₁₋₄-alkylene-,    (C₁₋₄-alkyl)HN—C₁₋₄-alkylene- and (C₁₋₄-alkyl)₂N—C₁₋₄-alkylene-;-   R^(2.4.2) is independently selected from among H, C₁₋₄-alkyl-,    C₁₋₄-haloalkyl-, C₃₋₆-cycloalkyl-, HO—C₁₋₄-alkylene-,    (C₁₋₄-alkyl)-O—C₁₋₄-alkylene-, H₂N—C₁₋₄-alkylene-,    (C₁₋₄-alkyl)HN—C₁₋₄-alkylene- and (C₁₋₄-alkyl)₂N—C₁₋₄-alkylene-.

Preferred are the above compounds of formula 1, wherein R^(2.5) istogether with R⁴ a group R^(2.5.a) and R^(2.5.a) is selected from among—C(R^(2.5.1))=, ═C(R^(2.5.1))— and —N═; and

-   R^(2.5.1) is independently selected from among H, C₁₋₄-alkyl-,    C₁₋₄-haloalkyl-, C₃₋₆-cycloalkyl-, HO—C₁₋₄-alkylene-,    (C₁₋₄-alkyl)-O—C₁₋₄-alkylene-, H₂N—C₁₋₄-alkylene-,    (C₁₋₄-alkyl)HN—C₁₋₄-alkylene- and (C₁₋₄-alkyl)₂N—C₁₋₄-alkylene-.

Preferred are the above compounds of formula 1, wherein R² is selectedfrom the Table 1 R²—Embodiments of the invention for R², R^(2.1),R^(2.1.1), R^(2.2), R^(2.3), R^(2.4) and R^(2.5) (if present):

TABLE 1 E # R² R^(2.1) R^(2.1.1) R^(2.2) R^(2.3-5)  1 R^(2.a) R^(2.1)R^(2.1.1.a) —  2 R^(2.a) R^(2.1) R^(2.1.1.b) —  3 R^(2.a) R^(2.1)R^(2.1.1.c) —  4 R^(2.b) R^(2.1.a) R^(2.1.1.a) —  5 R^(2.b) R^(2.1.a)R^(2.1.1.b) —  6 R^(2.b) R^(2.1.a) R^(2.1.1.c) —  7 R^(2.c) R^(2.1.a)R^(2.1.1.a) — —  8 R^(2.c) R^(2.1.a) R^(2.1.1.b) — —  9 R^(2.c)R^(2.1.a) R^(2.1.1.c) — — 10 R^(2.c) R^(2.1.a) R^(2.1.1.c) — R^(2.3.a)11 R^(2.c) R^(2.1.a) R^(2.1.1.c) — R^(2.4.a) 12 R^(2.c) R^(2.1.a)R^(2.1.1.c) — R^(2.5.a) 13 R^(2.d) R^(2.1.a) R^(2.1.1.a) — — 14 R^(2.d)R^(2.1.a) R^(2.1.1.b) — — 15 R^(2.d) R^(2.1.a) R^(2.1.1.c) — — 16R^(2.d) R^(2.1.a) R^(2.1.1.c) — R^(2.3.a) 17 R^(2.d) R^(2.1.a)R^(2.1.1.c) — R^(2.4.a) 18 R^(2.d) R^(2.1.a) R^(2.1.1.c) — R^(2.5.a) 19R^(2.e) R^(2.1.a) R^(2.1.1.a) R^(2.2.a) — 20 R^(2.e) R^(2.1.a)R^(2.1.1.b) R^(2.2.a) — 21 R^(2.e) R^(2.1.a) R^(2.1.1.c) R^(2.2.a) — 22R^(2.f) R^(2.1.a) R^(2.1.1.a) R^(2.2.a) — 23 R^(2.f) R^(2.1.a)R^(2.1.1.b) R^(2.2.a) — 24 R^(2.f) R^(2.1.a) R^(2.1.1.c) R^(2.2.a) — 25R^(2.g) R^(2.1.a) R^(2.1.1.a) R^(2.2.a) — 26 R^(2.g) R^(2.1.a)R^(2.1.1.b) R^(2.2.a) — 27 R^(2.g) R^(2.1.a) R^(2.1.1.c) R^(2.2.a) — 28R^(2.h) R^(2.1.a) R^(2.1.1.a) R^(2.2.a) — 29 R^(2.h) R^(2.1.a)R^(2.1.1.b) R^(2.2.a) — 30 R^(2.h) R^(2.1.a) R^(2.1.1.c) R^(2.2.a) — 31R^(2.e) R^(2.1.a) R^(2.1.1.c) — R^(2.3.a) 32 R^(2.e) R^(2.1.a)R^(2.1.1.c) — R^(2.4.a) 33 R^(2.e) R^(2.1.a) R^(2.1.1.c) — R^(2.5.a) 34R^(2.g) R^(2.1.a) R^(2.1.1.c) — R^(2.3.a) 35 R^(2.g) R^(2.1.a)R^(2.1.1.c) — R^(2.4.a) 36 R^(2.g) R^(2.1.a) R^(2.1.1.c) — R^(2.5.a) 37R^(2.h) R^(2.1.a) R^(2.1.1.c) — R^(2.3.a) 38 R^(2.h) R^(2.1.a)R^(2.1.1.c) — R^(2.4.a) 39 R^(2.h) R^(2.1.a) R^(2.1.1.c) — R^(2.5.a) 40R^(2.i) R^(2.1.a) R^(2.1.1.a) R^(2.2.a) — 41 R^(2.i) R^(2.1.a)R^(2.1.1.b) R^(2.2.a) — 42 R^(2.i) R^(2.1.a) R^(2.1.1.c) R^(2.2.a) — 43R^(2.j) R^(2.1.a) R^(2.1.1.a) R^(2.2.a) — 44 R^(2.j) R^(2.1.a)R^(2.1.1.b) R^(2.2.a) — 45 R^(2.j) R^(2.1.a) R^(2.1.1.c) R^(2.2.a) — 46R^(2.k) R^(2.1.a) R^(2.1.1.a) R^(2.2.a) — 47 R^(2.k) R^(2.1.a)R^(2.1.1.b) R^(2.2.a) — 48 R^(2.k) R^(2.1.a) R^(2.1.1.c) R^(2.2.a) — 49R^(2.l) R^(2.1.a) R^(2.1.1.a) R^(2.2.a) — 50 R^(2.l) R^(2.1.a)R^(2.1.1.b) R^(2.2.a) — 51 R^(2.l) R^(2.1.a) R^(2.1.1.c) R^(2.2.a) —

For a better understanding of the Table 1R²—Embodiments of the inventionexample (E#) 21, can also be read as a group R², wherein

-   R² is R^(2.e) and R^(2.e) is C_(5 or 6)-heteroaryl-, containing one,    two, three or four heteroatoms independently selected from among S,    S(O), S(O)₂, O and N, wherein carbon atoms of the ring are    optionally and independently from each other substituted with one,    two or three R^(2.1); wherein nitrogen atoms of the ring are    optionally and independently from each other substituted with one,    two or three R^(2.2); and    -   R^(2.1) is R^(2.1.a) and R^(2.1.a) is selected from among H,        halogen, NC—, O═, HO—, H-A-, H-A-C₁₋₄-alkylene-, R^(2.1.1)-A-,        C₁₋₄-alkyl-A-, C₃₋₆-cycloalkyl-A-, C₁₋₄-haloalkyl-A-,        R^(2.1.1)—C₁₋₄-alkylene-A-, C₁₋₄-alkyl-A-C₁₋₄-alkylene-,        C₃₋₆-cycloalkyl-A-C₁₋₄-alkylene-,        C₁₋₄-haloalkyl-A-C₁₋₄-alkylene-, is        R^(2.1.1)—C₁₋₄-alkylene-A-C₁₋₄-alkylene-,        R^(2.1.1)-A-C₁₋₄-alkylene-, HO—C₁₋₄-alkylene-A-,        HO—C₁₋₄-alkylene-A-C₁₋₄-alkylene-, C₁₋₄-alkyl-O—C₁₋₄-alkylene-A-        and C₁₋₄-alkyl-O—C₁₋₄-alkylene-A-C₁₋₄-alkylene-; and        -   R^(2.1.1) is R^(2.1.1.c) and R^(2.1.1.1.c) is phenyl or            selected from among

-   -   -   -   wherein carbon atoms of the ring are optionally and                independently from each other substituted with one, two                or three R^(2.1.1.1), wherein possibly available                nitrogen atoms of the ring are optionally and                independently from each other substituted with                R^(2.1.1.2); and            -   R^(2.1.1.1) is independently selected from among F, Cl,                Me, MeO— and cyclopropyl-; and            -   R^(2.1.1.2) is independently selected from among Me,                tetrahydrofuranylmethyl- and tetrahydropyranylmethyl;                and

-   R^(2.2) is R^(2.2.a) and R^(2.2.a) is independently selected from    among H-A-C₁₋₄-alkylene-, C₃₋₆-cycloalkyl-,    C₁₋₄-alkyl-A-C₁₋₄-alkylene-, C₃₋₆-cycloalkyl-A-C₁₋₄-alkylene-,    C₁₋₄-haloalkyl-A-C₁₋₄-alkylene-, R^(2.1.1)-A-C₁₋₄-alkylene-,    C₁₋₄-alkyl-S(O)₂—, C₁₋₄-alkyl-C(O)— and R^(2.1.1)-A-.

Preferred are the above compounds of formula 1, wherein R³ is R^(3.a)and R^(3.a) is H.

Preferred are the above compounds of formula 1, wherein R³ is R^(3.b)and R^(3.b) is F.

Preferred are the above compounds of formula 1, wherein R⁴ is R^(4.a)and R^(4.a) is H, F, Cl, phenyl-H₂C—O—, HO—, C₁₋₄-alkyl-,C₁₋₄-haloalkyl-, C₃₋₆-cycloalkyl-, C₁₋₄-alkyl-O— and C₁₋₄-haloalkyl-O—.

Preferred are the above compounds of formula 1, wherein R⁴ is R^(4.b)and R^(4.b) is H or F.

Preferred are the above compounds of formula 1, wherein R⁴ is R^(4.c)and R^(4.c) is F; preferably in ortho position.

Preferred are the above compounds of formula 1, wherein A is A^(a) andA^(a) is a bond or independently selected from

among —O—, —C(O)N(R⁵)—, —N(R⁵)C(O)—, —S(O)₂N(R⁵)—, —N(R⁵)S(O)₂—,—C(O)O—, —OC(O)—, —C(O)—, —S (O)₂—, —(R⁵)(O)S═N—, —(R⁵N═)(O)S— and—N═(O)(R⁵)S—, and R⁵ is R^(5.a) and R^(5.a) is independently selectedfrom among H, C₁₋₄-alkyl- and NC—.

Preferred is a compound of formula 1, wherein

-   R^(2.1) is R^(2.1.a) and R^(2.1.a) is selected from among H,    halogen, NC—, O═, HO—, H-A-, H-A-C₁₋₄-alkylene-, R^(2.1.1)-A-,    C₁₋₄-alkyl-A-, C₃₋₆-cycloalkyl-A-, C₁₋₄-haloalkyl-A-,    R^(2.1.1)—C₁₋₄-alkylene-A-, C₁₋₄-alkyl-A-C₁₋₄-alkylene-,    C₃₋₆-cycloalkyl-A-C₁₋₄-alkylene-, C₁₋₄-haloalkyl-A-C₁₋₄-alkylene-,    R^(2.1.1)—C₁₋₄-alkylene-A-C₁₋₄-alkylene-,    R^(2.1.1)-A-C₁₋₄-alkylene-, HO—C₁₋₄-alkylene-A-,    HO—C₁₋₄-alkylene-A-C₁₋₄-alkylene-, C₁₋₄-alkyl-O—C₁₋₄-alkylene-A— and    C₁₋₄-alkyl-O—C₁₋₄-alkylene-A-C₁₋₄-alkylene-; and    -   R^(2.1.1) is R^(2.1.1.a) and R^(2.1.1.a) is selected from among        -   aryl-, optionally substituted independently from each other            with one, two or three residues independently selected from            R^(2.1.1.1);        -   C₅₋₁₀-heteroaryl-, containing one, two, three or four            heteroatoms selected independently from S, S(O), S(O)₂, O            and N, wherein carbon atoms of the ring are optionally and            independently from each other substituted with one, two or            three R^(2.1.1.1); wherein nitrogen atoms of the ring are            optionally and independently from each other substituted            with one, two or three R^(2.1.1.2);        -   C₅₋₁₀-heterocyclyl-, containing one, two, three or four            heteroatoms selected independently from S, S(O), S(O)₂, O            and N and the ring is fully or partially saturated, wherein            carbon atoms of the ring are optionally and independently            from each other substituted with one, two or three            R^(2.1.1.1); wherein nitrogen atoms of the ring are            optionally and independently from each other substituted            with one, two or three R^(2.1.1.2); and    -   R^(2.1.1.1) is independently selected from among halogen, HO—,        O═, C₁₋₄-alkyl-, C₁₋₄-alkyl-O—, C₁₋₄-haloalkyl-,        C₁₋₄-haloalkyl-O— and C₃₋₆-cycloalkyl-; and    -   R^(2.1.1.2) is independently selected from among O═,        C₁₋₄-alkyl-, C₁₋₄-haloalkyl-; C₃₋₆-cycloalkyl-,        C₁₋₄-alkyl-O—C₁₋₄-alkyl-, H(O)C—, C₁₋₄-alkyl-(O)C—,        tetrahydrofuranylmethyl- and tetrahydropyranylmethyl.

Preferred is a compound of formula 1, wherein R² is R^(2.d) and R^(2.d)is phenyl; optionally substituted with one, two or three residuesindependently selected from R^(2.1) and

-   R^(2.1) is R^(2.1.a) and R^(2.1.a) is selected from among H,    halogen, NC—, O═, HO—, H-A-, H-A-C₁₋₄-alkylene-, R^(2.1.1)-A-,    C₁₋₄-alkyl-A-, C₃₋₆-cycloalkyl-A-, C₁₋₄-haloalkyl-A-,    R^(2.1.1)—C₁₋₄-alkylene-A-, C₁₋₄-alkyl-A-C₁₋₄-alkylene-,    C₃₋₆-cycloalkyl-A-C₁₋₄-alkylene-, C₁₋₄-haloalkyl-A-C₁₋₄-alkylene-,    R^(2.1.1)—C₁₋₄-alkylene-A-C₁₋₄-alkylene-,    R^(2.1.1)-A-C₁₋₄-alkylene-, HO—C₁₋₄-alkylene-A-,    HO—C₁₋₄-alkylene-A-C₁₋₄-alkylene-, C₁₋₄-alkyl-O—C₁₋₄-alkylene-A— and    C₁₋₄-alkyl-O—C₁₋₄-alkylene-A-C₁₋₄-alkylene-; and    -   R^(2.1.1) is R^(2.1.1.a) and R^(2.1.1.a) is selected from among        -   aryl-, optionally substituted independently from each other            with one, two or three residues independently selected from            R^(2.1.1.1);        -   C₅₋₁₀-heteroaryl-, containing one, two, three or four            heteroatoms selected independently from S, S(O), S(O)₂, O            and N, wherein carbon atoms of the ring are optionally and            independently from each other substituted with one, two or            three R^(2.1.1.1); wherein nitrogen atoms of the ring are            optionally and independently from each other substituted            with one, two or three R^(2.1.1.2);        -   C₅₋₁₀-heterocyclyl-, containing one, two, three or four            heteroatoms selected independently from S, S(O), S(O)₂, O            and N and the ring is fully or partially saturated, wherein            carbon atoms of the ring are optionally and independently            from each other substituted with one, two or three            R^(2.1.1.1); wherein nitrogen atoms of the ring are            optionally and independently from each other substituted            with one, two or three R^(2.1.1.2); and    -   R^(2.1.1.1) is independently selected from among halogen, HO—,        O═, C₁₋₄-alkyl-, C₁₋₄-alkyl-O—, C₁₋₄-haloalkyl-,        C₁₋₄-haloalkyl-O— and C₃₋₆-cycloalkyl-; and    -   R^(2.1.1.2) is independently selected from among O═,        C₁₋₄-alkyl-, C₁₋₄-haloalkyl-; C₃₋₆-cycloalkyl-,        C₁₋₄-alkyl-O—C₁₋₄-alkyl-, H(O)C—, C₁₋₄-alkyl-(O)C—,        tetrahydrofuranylmethyl- and tetrahydropyranylmethyl.

Preferred is a compound of formula 1, wherein

-   R¹ is independently selected from among H, C₁₋₄-alkyl-, halogen,    HO—, C₁₋₄-alkyl-O—, H₂N—, C₁₋₆-alkyl-HN—, (C₁₋₆-alkyl)₂N— and    C₁₋₆-alkyl-C(O)HN—;-   or two R¹ are together C₁₋₄-alkylene;-   R² is selected of the examples of the Table 1R²—Embodiments of the    invention; preferably examples (E#) 7-51, preferably one of the    groups selected from among 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17,    18 or 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33,    34, 35, 36, 37, 38, 39 or 40, 41, 42, 43, 44, 45, 45, 46, 47, 48,    49, 50- and 51;-   R³ is H or F;-   R⁴ is independently selected from among H, F, Cl, phenyl-H₂C—O—,    HO—, C₁₋₆-alkyl-, C₁₋₆-haloalkyl-, C₃₋₈-cycloalkyl-, C₁₋₆-alkyl-O—,    C₁₋₆-haloalkyl-O—, C₁₋₆-alkyl-HN—, (C₁₋₆-alkyl)₂-HN—,    C₁₋₆-alkyl-HN—C₁₋₄-alkylene- and (C₁₋₆-alkyl)₂-HN—C₁₋₄-alkylene-;-   A is a bond or independently selected from among —O—, —S—, —N(R⁵)—,    —C(O)N(R⁵)—, —N(R⁵)C(O)—, —S(O)₂N(R⁵)—, —N(R⁵)S(O)₂—,    —S(O)(═NR⁵)—N(R⁵)—, —N(R⁵)(NR⁵═) S(O)—, —S(═NR⁵)₂—N(R⁵)—,    —N(R⁵)(NR⁵═)₂S—, —C(R⁵)═C(R⁵)—, —C≡C—, —C(O)O—, —OC(O)—, —C(O)—,    —S(O)—, S(O)₂—, —S(═NR⁵)—, —S(O)(═NR⁵)—, —S(═NR⁵)₂—, —(R⁵)(O)S═N—,    —(R⁵N═)(O)S— and —N═(O)(R⁵)S—;-   R⁵ is independently selected from among H, C₁₋₆-alkyl- and NC—;    or a salt thereof.

Preferred is a compound of formula 1, wherein

-   R¹ is R^(1.a) and R^(1.a) is independently selected from among H,    C₁₋₄-alkyl-, F— and HO—.-   or two R¹ are together C₁₋₄-alkylene;-   R² is selected of the examples of the Table 1R²—Embodiments of the    invention; preferably examples (E#) 7-51, preferably one of the    groups selected from among 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17,    18 or 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33,    34, 35, 36, 37, 38, 39 or 40, 41, 42, 43, 44, 45, 45, 46, 47, 48,    49, 50- and 51;-   R³ is H, F;-   R⁴ is R^(4.a) and R^(4.a) is H, F, Cl, phenyl-H₂C—O—, HO—,    C₁₋₄-alkyl-, C₁₋₄-haloalkyl-, C₃₋₆-cycloalkyl-, C₁₋₄-alkyl-O— and    C₁₋₄-haloalkyl-O—;-   A is a bond or independently selected from among —O—, —S—, —N(R⁵)—,    —C(O)N(R⁵)—, —N(R⁵)C(O)—, —S(O)₂N(R⁵)—, —N(R⁵)S(O)₂—,    —S(O)(═NR⁵)—N(R⁵)—, —N(R⁵)(NR⁵═) S(O)—, —S(═NR⁵)₂—N(R⁵)—,    —N(R⁵)(NR⁵═)₂S—, —C(R⁵)═C(R⁵)—, —C≡C—, —C(O)O—, —OC(O)—, —C(O)—,    —S(O)—, S(O)₂—, —S(═NR⁵)—, —S(O)(═NR⁵)—, —S(═NR⁵)₂—, —(R⁵)(O)S═N—,    —(R⁵N═)(O)S— and —N═(O)(R⁵)S—;-   R⁵ is independently selected from among H, C₁₋₆-alkyl- and NC—;    or a salt thereof.

Preferred is a compound of formula 1, wherein

-   R¹ is R^(1.a) and R^(1.a) is independently selected from among H,    C₁₋₄-alkyl-, F— and HO—.-   or two R¹ are together C₁₋₄-alkylene;-   R² is selected of the examples of the Table 1R²—Embodiments of the    invention; preferably examples (E#) 7-51, preferably one of the    groups selected from among 13, 14, 15, 16, 17, 18 or 25, 26, 27, 28,    29, 30, 34, 35, 36, 37, 38, 39 or 43, 44, 45, 46, 47- and 48;-   R³ is H or F;-   R⁴ is R^(4.a) and R^(4.a) is H, F, Cl, phenyl-H₂C—O—, HO—,    C₁₋₄-alkyl-, C₁₋₄-haloalkyl-, C₃₋₆-cycloalkyl-, C₁₋₄-alkyl-O— and    C₁₋₄-haloalkyl-O—;-   A is A^(a) and A^(a) is a bond or independently selected from    -   among —O—, —C(O)N(R⁵)—, —N(R⁵)C(O)—, —S(O)₂N(R⁵)—, —N(R⁵)S(O)₂—,        —C(O)O—, —OC(O)—, —C (O)—, S(O)₂—, —(R⁵)(O)S═N—, —(R⁵N═)(O)S—        and —N═(O)(R⁵)S—;-   R⁵ is R^(5.a) and R^(5.a) is independently selected from among H,    C₁₋₄-alkyl- and NC—;    or a salt thereof.

Preferred is a compound of formula 1, wherein

-   R¹ is R^(1.b) and R^(1.b) is H; or two R¹ are together —CH₂—;-   R² is selected of the examples of the Table 1R²—Embodiments of the    invention; preferably examples (E#) 7-51, preferably one of the    groups selected from among 13, 14, 15, 16, 17, 18 or 25, 26, 27, 28,    29, 30, 34, 35, 36, 37, 38, 39 or 43, 44, 45, 46, 47- and 48;-   R³ is H or F;-   R⁴ is R^(4.b) and R^(4.b) is H or F;-   A is A^(a) and A^(a) is a bond or independently selected from    -   among —O—, —C(O)N(R⁵)—, —N(R⁵)C(O)—, —S(O)₂N(R⁵)—, —N(R⁵)S(O)₂—,        —C(O)O—, —OC(O)—, —C (O)—, S(O)₂—, —(R⁵)(O)S═N—, —(R⁵N═)(O)S—        and —N═(O)(R⁵)S—;-   R⁵ is R^(5.a) and R^(5.a) is independently selected from among H,    C₁₋₄-alkyl- and NC—;    or a salt thereof.

Preferred is a compound of formula 1, wherein

-   R¹ is R^(1.b) and R^(1.b) is H; or two R¹ are together —CH₂—;-   R² is selected of the examples of the Table 1R²—Embodiments of the    invention; preferably examples (E#) 7-51, preferably one of the    groups selected from among 13-15, 16-18 or 25-30, 34-39- and 43-48;-   R³ is H or F;-   R⁴ is R^(4.b) and R^(4.b) is H or F;-   A is A^(a) and A^(a) is a bond or independently selected from    -   among —O—, —C(O)N(R⁵)—, —N(R⁵)C(O)—, —S(O)₂N(R⁵)—, —N(R⁵)S(O)₂—,        —C(O)O—, —OC(O)—, —C(O)—, S(O)₂—, —(R⁵)(O)S═N—, —(R⁵N═)(O)S— and        —N═(O)(R⁵)S—;-   R⁵ is R^(5.a) and R^(5.a) is independently selected from among H,    C₁₋₄-alkyl- and NC—;    or a salt thereof.

Preferred is a compound of formula 1, wherein

-   R¹ is R^(1.b) and R^(1.b) is H; or two R¹ are together —CH₂—;-   R² is selected from among    -   R^(2.1);    -   phenyl-; optionally substituted with one or two residues        independently selected from R^(2.1); optionally substituted with        one R^(2.3);    -   C₅-heteroaryl-; containing two or three independently selected        from among S, O and N, wherein carbon atoms of the ring are        optionally and independently from each other substituted with        one R^(2.1); wherein nitrogen atoms of the ring are optionally        and independently from each other substituted with one R^(2.2);    -   monocyclic C₆-heterocyclyl containing one or two nitrogen atoms,        wherein the ring is fully or partially saturated, wherein carbon        atoms of the ring are optionally and independently from each        other substituted with one R^(2.1); wherein nitrogen atoms of        the ring are optionally and independently from each other        substituted with one R^(2.2); and bicyclic        C_(9 or 10)-heterocyclyl-; containing one, two, three or four        heteroatoms independently selected from among S(O)₂, O and N,        wherein the ring is fully or partially saturated, wherein carbon        atoms of the ring are optionally and independently from each        other substituted with one, two or three R^(2.1); wherein        nitrogen atoms of the ring are optionally and independently from        each other substituted with one R^(2.2);    -   R^(2.1) is independently selected from among halogen, NC—, O═,        H-A-, H-A-C₁₋₄-alkylene-, R^(2.1.1)-A-, C₁₋₄-alkyl-A-,        C₃₋₆-cycloalkyl-A-, R^(2.1.1)—C₁₋₄-alkylene-A-,        C₁₋₄-alkyl-A-C₁₋₄-alkylene-, HO—C₁₋₄-alkylene-A-C₁₋₄-alkylene-;        preferably F, NC—, O═, H-A-, H-A-CH₂—, R^(2.1.1)-A-, H₃C-A-,        H₃C—CH₂-A-, Cyclopropyl-A-, R^(2.1.1)—CH₂—CH₂-A-,        R^(2.1.1)—CH₂-A-, H₃C-A-CH₂—CH₂— and HO—C₄-alkylene-A-CH₂—;        -   R^(2.1.1) is independently selected from among            -   phenyl-; and            -   C_(5 or 6)-heterocyclyl-; containing one or two                heteroatoms independently selected from among O and N,                wherein the ring is fully or partially saturated,                wherein nitrogen atoms of the ring are optionally and                independently from each other substituted with one                C₁₋₄-alkyl-; preferably H₃C—;    -   R^(2.2) is independently selected from among H-A-C₁₋₄-alkylene-,        C₃₋₆-cycloalkyl-, C₁₋₄-alkyl-A-C₁₋₄-alkylene-,        R^(2.1.1)-A-C₁₋₄-alkylene-, C₁₋₄-alkyl-C(O)—; preferably        H-A-CH₂—, H-A-CH₂—CH₂—, cyclopropyl-, H₃C-A-CH₂—CH₂—,        R^(2.1.1)-A-CH₂— and H₃C—C(O)—;    -   R^(2.3) and R⁴ are together a group selected from    -   among —N(R^(2.3.1))—, —C(O)N(R^(2.3.2))— and —N(R^(2.3.1))C(O)—;        -   R^(2.3.1) is independently selected from among H— and H₃C—;-   R³ is H or F;-   R⁴ is R^(4.b) and R^(4.b) is H or F;-   A is a bond or independently selected from    -   among —O—, —C(O)N(R⁵)—, —N(R⁵)C(O)—, —S(O)₂N(R⁵)—, —N(R⁵)S(O)₂—,        —C(O)O—, —OC(O)—, —C(O)—, —S(O)₂— and —N═(O)(R⁵)S—;-   R⁵ is independently selected from among H— and C₁₋₄-alkyl-;    or a salt thereof.

Particularly preferred are the above compounds of formula 1, wherein R³is H and R⁴ is F.

Particularly preferred are the above compounds of formula 1, wherein R³is H and R⁴ is H.

-   Preferred are the above compounds of formula 1, wherein R² is    R^(2.t) and R^(2.t) is selected from among the substituents (a1) to    (g1) particularly preferred (a1) and (b1),

-   wherein carbon atoms of the rings are optionally and independently    from each other substituted with one, two or three R^(2.1); wherein    a nitrogen atom of the ring is optionally substituted with R^(2.2).-   Preferred are the above compounds of formula 1, wherein R² is    R^(2.t) and R^(2.t) is selected from among the substituents (a2) to    (g2)

-   wherein carbon atoms of the rings are optionally and independently    from each other substituted with one, two or three R^(2.1); wherein    a nitrogen atom of the ring is optionally substituted with R^(2.2).-   Preferred are the above compounds of formula 1, wherein R² is    R^(2.r) and R^(2.r) is selected from among the substituents (a2) and    (b2)

-   wherein carbon atoms of the ring are optionally and independently    from each other substituted with one, two or three R^(2.1);    preferably one or two, wherein the nitrogen atom of the ring are    optionally substituted with R^(2.2).

Preferably R^(2.1) denotes a group selected from among —CN, F,—SO₂—C₁₋₂-alkyl, ═O, —CH₃, —NH—SO₂—CH₃, —SO₂—NH₂, —CONH₂, and—C₂H₅—O—CH₃.

-   Preferably R²² denotes —CH₃.-   Particularly preferred R^(2.1) denotes a group selected from among    —CN, F, —SO₂—C₁₋₂-alkyl, ═O, —CH₃, —NH—SO₂—CH₃, —SO₂—NH₂, —CONH₂,    and —C₂H₅—O—CH₃, and-   R²² denotes —CH₃.-   Preferred are the above compounds of formula 1, wherein R² is    R^(2.s) and R^(2.s) is selected from among the substituents (a3) and    (b3)

-   Preferred are the compounds of formula 1, wherein the compounds are    selected from the group consisting of examples 1 and 4.-   Preferred are the above compounds of formula 1, in its    enantiomerically pure form of formula 1′

wherein R¹, R², R³ and R⁴ have the above mentioned meaning.

USED TERMS AND DEFINITIONS

Terms not specifically defined herein should be given the meanings thatwould be given to them by one of skill in the art in light of thedisclosure and the context. As used in the specification, however,unless specified to the contrary, the following terms have the meaningindicated and the to following conventions are adhered to.

In the groups, radicals, or moieties defined below, the number of carbonatoms is often specified preceding the group, for example, C₁₋₆-alkylmeans an alkyl group or radical having 1 to 6 carbon atoms.

In general in single groups like HO, H₂N, S(O), S(O)₂, NC (cyano), HOOC,F₃C or the like, the skilled artisan can see the radical attachmentpoint(s) to the molecule from the free valences of the group itself. Forcombined groups comprising two or more subgroups, the last namedsubgroup is the radical attachment point, for example, the substituent“aryl-C₁₋₄-alkyl-” means an aryl group which is bound to aC₁₋₄-alkyl-group, the latter of which is bound to the core or to thegroup to which the substituent is attached.

Alternatively “*” indicates within a chemical entity the binding site,i.e. the point of attachment

In case a compound of the present invention is depicted in form of achemical name and as a formula in case of any discrepancy the formulashall prevail. An asterisk is may be used in sub-formulas to indicatethe bond which is connected to the core molecule as defined.

Many of the followings terms may be used repeatedly in the definition ofa formula or group and in each case have one of the meanings givenabove, independently of one another.

The term “substituted” as used herein, means that any one or morehydrogens on the designated atom is replaced with a selection from theindicated group, provided that the designated atom's normal valence isnot exceeded, and that the substitution results in a stable compound.

The expressions “prevention”, “prophylaxis”, “prophylactic treatment” or“preventive treatment” used herein should be understood synonymous andin the sense that the risk to develop a condition mentioned hereinbeforeis reduced, especially in a patient having elevated risk for saidconditions or a corresponding anamnesis, e.g. elevated risk ofdeveloping metabolic disorder such as diabetes or obesity or anotherdisorder mentioned herein. Thus the expression “prevention of a disease”as used herein means the management and care of an individual at risk ofdeveloping the disease prior to the clinical onset of the disease. Thepurpose of prevention is to combat the development of the disease,condition or disorder, and includes the administration of the activecompounds to prevent or delay the onset of the symptoms or complicationsand to prevent or delay the development of related diseases, conditionsor disorders. Success of said preventive treatment is reflectedstatistically by reduced incidence of said condition within a patientpopulation at risk for this condition in comparison to an equivalentpatient population without preventive treatment.

The expression “treatment” or “therapy” means therapeutic treatment ofpatients having already developed one or more of said conditions inmanifest, acute or chronic form, including symptomatic treatment inorder to relieve symptoms of the specific indication or causal treatmentin order to reverse or partially reverse the condition or to delay theprogression of the indication as far as this may be possible, dependingon the condition and the severity thereof. Thus the expression“treatment of a disease” as used herein means the management and care ofa patient having developed the disease, condition or disorder. Thepurpose of treatment is to combat the disease, condition or disorder.Treatment includes the administration of the active compounds toeliminate or control the disease, condition or disorder as well as toalleviate the symptoms or complications associated with the disease,condition or disorder.

Unless specifically indicated, throughout the specification and theappended claims, a given chemical formula or name shall encompasstautomers and all stereo, optical and geometrical isomers (e.g.enantiomers, diastereomers, E/Z isomers etc. . . . ) and racematesthereof as well as mixtures in different proportions of the separateenantiomers, mixtures of diastereomers, or mixtures of any of theforegoing forms where such isomers and enantiomers exist, as well assalts, including pharmaceutically acceptable salts thereof and solvatesthereof such as for instance hydrates including solvates of the freecompounds or solvates of a salt of the compound.

As used herein the term “prodrug” refers to (i) an inactive form of adrug that exerts its effects after metabolic processes within the bodyconverting it to a usable or active form, or (ii) a substance that givesrise to a pharmacologically active metabolite, although not itselfactive (i.e. an inactive precursor).

The terms “prodrug” or “prodrug derivative” mean a covalently-bondedderivative, carrier or precursor of the parent compound or active drugsubstance which undergoes at least some biotransformation prior toexhibiting its pharmacological effect(s). Such prodrugs either havemetabolically cleavable or otherwise convertible groups and are rapidlytransformed in vivo to yield the parent compound, for example, byhydrolysis in blood or by activation via oxidation as in case ofthioether groups. Most common prodrugs include esters and amide analogsof the parent compounds. The prodrug is formulated with the objectivesof improved chemical stability, improved patient acceptance andcompliance, improved bioavailability, prolonged duration of action,improved organ selectivity, improved formulation (e.g., increasedhydrosolubility), and/or decreased side effects (e.g., toxicity). Ingeneral, prodrugs themselves have weak or no biological activity and arestable under ordinary conditions. Prodrugs can be readily prepared fromthe parent compounds using methods known in the art, such as thosedescribed in A Textbook of Drug Design and Development,Krogsgaard-Larsen and H. Bundgaard (eds.), Gordon & Breach, 1991,particularly Chapter 5: “Design and Applications of Prodrugs”; Design ofProdrugs, H. Bundgaard (ed.), Elsevier, 1985; Prodrugs: Topical andOcular Drug Delivery, K. B. Sloan (ed.), Marcel Dekker, 1998; Methods inEnzymology, K. Widder et al. (eds.), Vol. 42, Academic Press, 1985,particularly pp. 309-396; Burger's Medicinal Chemistry and DrugDiscovery, 5th Ed., M. Wolff (ed.), John Wiley & Sons, 1995,particularly Vol. 1 and pp. 172-178 and pp. 949-982; Pro-Drugs as NovelDelivery Systems, T. Higuchi and V. Stella (eds.), Am. Chem. Soc., 1975;Bioreversible Carriers in Drug Design, E. B. Roche (ed.), Elsevier,1987, each of which is incorporated herein by reference in theirentireties.

The term “pharmaceutically acceptable prodrug” as used herein means aprodrug of a compound of the invention which is, within the scope ofsound medical judgment, suitable for use in contact with the tissues ofhumans and lower animals without undue toxicity, irritation, allergicresponse, and the like, commensurate with a reasonable benefit/riskratio, and effective for their intended use, as well as the zwitterionicforms, where possible.

The phrase “pharmaceutically acceptable” is employed herein to refer tothose compounds, materials, compositions, and/or dosage forms which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of human beings and animals without excessive toxicity,irritation, allergic response, or other problem or complication, andcommensurate with a reasonable benefit/risk ratio.

As used herein, “pharmaceutically acceptable salts” refer to derivativesof the disclosed compounds wherein the parent compound is modified bymaking acid or base salts thereof. Examples of pharmaceuticallyacceptable salts include, but are not limited to, mineral or organicacid salts of basic residues such as amines; alkali or organic salts ofacidic residues such as carboxylic acids; and the like. For example,such salts include salts from ammonia, L-arginine, betaine, benethamine,benzathine, calcium hydroxide, choline, deanol, diethanolamine(2,2′-iminobis(ethanol)), diethylamine, 2-(diethylamino)-ethanol,2-aminoethanol, ethylenediamine, N-ethyl-glucamine, hydrabamine,1H-imidazole, lysine, magnesium hydroxide,4-(2-hydroxyethyl)-morpholine, piperazine, potassium hydroxide,1-(2-hydroxyethyl)-pyrrolidine, sodium hydroxide, triethanolamine(2,2′,2″-nitrilotris(ethanol)), tromethamine, zinc hydroxide, aceticacid, 2.2-dichloro-acetic acid, adipic acid, alginic acid, ascorbicacid, L-aspartic acid, benzenesulfonic acid, benzoic acid,2,5-dihydroxybenzoic acid, 4-acetamido-benzoic acid, (+)-camphoric acid,(+)-camphor-10-sulfonic acid, carbonic acid, cinnamic acid, citric acid,cyclamic acid, decanoic acid, dodecylsulfuric acid,ethane-1,2-disulfonic acid, ethanesulfonic acid,2-hydroxy-ethanesulfonic acid, ethylenediaminetetraacetic acid, formicacid, fumaric acid, galactaric acid, gentisic acid, D-glucoheptonicacid, D-gluconic acid, D-glucuronic acid, glutamic acid, glutaric acid,2-oxo-glutaric acid, glycerophosphoric acid, glycine, glycolic acid,hexanoic acid, hippuric acid, hydrobromic acid, hydrochloric acid,isobutyric acid, DL-lactic acid, lactobionic acid, lauric acid, lysine,maleic acid, (−)-L-malic acid, malonic acid, DL-mandelic acid,methanesulfonic acid, galactaric acid, naphthalene-1,5-disulfonic acid,naphthalene-2-sulfonic acid, 1-hydroxy-2-naphthoic acid, nicotinic acid,nitric acid, octanoic acid, oleic acid, orotic acid, oxalic acid,palmitic acid, pamoic acid (embonic acid), phosphoric acid, propionicacid, (−)-L-pyroglutamic acid, salicylic acid, 4-amino-salicylic acid,sebacic acid, stearic acid, succinic acid, sulfuric acid, tannic acid,(+)-L-tartaric acid, thiocyanic acid, p-toluenesulfonic acid andundecylenic acid. Further pharmaceutically acceptable salts can beformed with cations from metals like aluminium, calcium, lithium,magnesium, potassium, sodium, zinc and the like. (also seePharmaceutical salts, Berge, S. M. et al., J. Pharm. Sci., (1977), 66,1-19).

The pharmaceutically acceptable salts of the present invention can besynthesized from the parent compound which contains a basic or acidicmoiety by conventional chemical methods. Generally, such salts can beprepared by reacting the free acid or base forms of these compounds witha sufficient amount of the appropriate base or acid in water or in anorganic diluent like ether, ethyl acetate, ethanol, isopropanol, oracetonitrile, or a mixture thereof.

Salts of other acids than those mentioned above which for example areuseful for purifying or isolating the compounds of the present invention(e.g. trifluoro acetate salts,) also comprise a part of the invention.

The term halogen generally denotes fluorine, chlorine, bromine andiodine.

The term “C_(1-n)-alkyl”, wherein n is an integer selected from among 2,3, 4, 5 or 6, either alone or in combination with another radicaldenotes an acyclic, saturated, branched or linear hydrocarbon radicalwith 1 to n C atoms. For example the term C₁₋₅-alkyl embraces theradicals H₃C—, H₃C—CH₂—, H₃C—CH₂—CH₂—, H₃C—CH(CH₃)—, H₃C—CH₂—CH₂—CH₂—,H₃C—CH₂—CH(CH₃)—, H₃C—CH(CH₃)—CH₂—, H₃C—C(CH₃)₂—, H₃C—CH₂—CH₂—CH₂—CH₂—,H₃C—CH₂—CH₂—CH(CH₃)—, H₃C—CH₂—CH(CH₃)—CH₂—, H₃C—CH(CH₃)—CH₂—CH₂—,H₃C—CH₂—C(CH₃)₂—, H₃C—C(CH₃)—CH₂—, H₃C—CH(CH₃)—CH(CH₃)— andH₃C—CH₂—CH(CH₂CH₃)—.

The term “C_(1-n)-alkylene” wherein n is an integer selected from among2, 3, 4, 5 or 6, preferably 4 or 6, either alone or in combination withanother radical, denotes an acyclic, straight or branched chain divalentalkyl radical containing from 1 to n carbon atoms. For example the termC₁₋₄-alkylene

includes —CH₂—, —CH₂—CH₂—, —CH(CH₃)—, —CH₂—CH₂—CH₂—, —C(CH₃)₂—,—CH(CH₂CH₃)—, —CH(CH₃)—C H₂—, —CH₂—CH(CH₃)—, —CH₂—CH₂—CH₂—CH₂—,—CH₂—CH₂—CH(CH₃)—, —CH(CH₃)—CH₂—CH₂—, —CH₂—CH (CH₃)—CH₂—, —CH₂—C(CH₃)₂—,—C(CH₃)₂—CH₂—, —CH(CH₃)—CH(CH₃)—, —CH₂—CH(CH₂CH₃)—, —CH(CH₂CH₃)—CH₂—,—CH(CH₂CH₂CH₃)—, —CH(CH(CH₃))₂— and —C(CH₃)(CH₂CH₃)—.

The term “C_(3-n)-cycloalkyl”, wherein n is an integer selected fromamong 4, 5, 6, 7 or 8, preferably 4, 5 or 6, either alone or incombination with another radical denotes a cyclic, saturated, unbranchedhydrocarbon radical with 3 to 8 C atoms. For example the termC₃₋₈-cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl, cyclooctyl.

By the term “halo” added to a “alkyl”, “alkylene” or “cycloalkyl” group(saturated or unsaturated) is such a alkyl or cycloalkyl group whereinone or more hydrogen atoms are replaced by a halogen atom selected fromamong fluorine, chlorine or bromine, preferably fluorine and chlorine,particularly preferred is fluorine. Examples include: H₂FC—, HF₂C—,F₃C—.

The term “aryl” as used herein, either alone or in combination withanother radical, denotes a carbocyclic aromatic monocyclic groupcontaining 6 carbon atoms which may be further fused to a second five-or six-membered, carbocyclic group which may be aromatic, saturated orunsaturated. Aryl includes, but is not limited to, phenyl, indanyl,indenyl, naphthyl, anthracenyl, phenanthrenyl, tetrahydronaphthyl anddihydronaphthyl.

The term “C₅₋₁₀-heterocyclyl” means a saturated or unsaturated mono- orpolycyclic-ring systems including aromatic ring system containing one ormore heteroatoms independently selected from among N, O or S(O)_(r),wherein r=0, 1 or 2, consisting of 5 to 10 ring atoms wherein none ofthe heteroatoms is part of the aromatic ring. The term “heterocyclyl” isintended to include all the possible isomeric forms. Thus, the term“heterocyclyl” includes the following exemplary structures which are notdepicted as radicals as each form may be attached through a covalent(single or double) bond to any atom so long as appropriate valences aremaintained:

The term “C₅₋₁₀-heteroaryl” means a mono- or polycyclic-ring systemscontaining one or more heteroatoms independently selected from among N,O or S(O)_(r), wherein r=0, 1 or 2, consisting of 5 to 10 ring atomswherein at least one of the heteroatoms is part of aromatic ring. Theterm “heteroaryl” is intended to include all the possible isomericforms. Thus, the term “heteroaryl” includes the following exemplarystructures which are not depicted as radicals as each form may beattached through a covalent bond to any atom so long as appropriatevalences are maintained:

Preparation

General Synthetic Methods

The invention also provides processes for making a compound of FormulaI. In all methods, unless specified otherwise, R¹, R² and n in theformulas below shall have the meaning of R¹, R² and n in Formula I ofthe invention described herein above.

Optimal reaction conditions and reaction times may vary depending on theparticular reactants used. Unless otherwise specified, solvents,temperatures, pressures, and other reaction conditions is may be readilyselected by one of ordinary skill in the art. Specific procedures areprovided in the Synthetic Examples section. Typically, reaction progressmay be monitored by thin layer chromatography (TLC) or LC-MS, ifdesired, and intermediates and products may be purified bychromatography on silica gel, HPLC and/or by recrystallization. Theexamples which follow are illustrative and, as recognized by one skilledin the art, particular reagents or conditions could be modified asneeded for individual compounds without undue experimentation. Startingmaterials and intermediates used, in the methods below, are eithercommercially available or easily prepared from commercially availablematerials by those skilled in the art.

A compound of Formula V, VII and IX may be made by the method outlinedin Scheme 1:

As illustrated in Scheme 1, a compound of Formula II, wherein PGrepresents a protecting group (e.g. tert-butoxycarbonyl), may be reactedwith an aqueous ammonia solution, using standard literature proceduresfor the formation of an amide. For example, in the presence of a basesuch as N-methyl-morpholine or N-ethyl-morpholine and an activatingagent such as O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HATU) orO-(Benzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumtetrafluoroborate(TBTU). The reaction is conveniently carried out in a suitable solventsuch as N,N-dimethylformamide. Standard peptide coupling reactions knownin the art (see for example M. Bodanszky, 1984, The Practice of PeptideSynthesis, Springer-Verlag) may be employed in these syntheses.

Dehydration of an amide such as in a compound of Formula III or FormulaIX to the corresponding nitrile of Formula IV or VII may be carried outby use of a dehydration agent such as (methoxycarbonylsulfamoyl)triethylammonium hydroxide, in a suitable solvent such as dichloromethane (DCM).

Reacting an acid of Formula VI using standard literature procedures forthe formation of an amide, for example in the presence of a base such asN,N-diisopropylethylamine (DIPEA) and an activating agent such as HATUor TBTU, with an amine of Formula V or VIII in a suitable solvent,provides a compound of Formula VII or IX. Standard peptide couplingreactions known in the art to (see for example M. Bodanszky, 1984, ThePractice of Peptide Synthesis, Springer-Verlag) may be employed in thesesyntheses.

The protection and deprotection of functional groups is described in‘Protective Groups in Organic Synthesis’, T. W. Greene and P. G. M.Wuts, Wiley-Interscience. For example, for the deprotection oftert-butoxycarbonyl, an acid such as formic acid, trifluoroacetic acid,p-toluenesulfonic acid or HCl may be used in a suitable solvent such aswater, DCM or dioxane. Another method to deprotect tert-butoxycarbonylis the reaction with trimethyliodosilane or trimethylchlorosilane incombination with sodium iodide in an appropriate solvent likeacetonitrile, DMF or DCM.

During the reaction sequences depicted in Scheme 1 and Scheme 2 ahydroxy group (X═OH) can be converted to a trifluoromethanesulfonylgroup (X=OTf) at any level. Especially, a compound IX with X=OH istransformed to the appropriate triflate (X=OTf) by reaction withN,N-bis-(trifluoromethanesulfonyl) aniline, or trifluoromethanesulfonylchloride or anhydride, in the presence of an organic base e.g.triethylamine, morpholine, piperidine, DIPEA in an appropriate anhydroussolvent, e.g. DCM.

As illustrated in Scheme 2, (transition) metal catalyzed reaction of acompound of Formula VII or IX wherein X is I, Br, Cl or OTf, provides acompound of Formula X or XI. For example, reaction with a boronic acidor the corresponding boronic acid ester, in a suitable solvent such asacetonitrile, in the presence of a suitable catalyst such as1,1-bis(di-tert-butylphosphino)ferrocene palladium dichloride and asuitable base such as K₂CO₃ provides a compound of Formula X or XI.Alternatively, reaction of a compound of Formula VII or IX, wherein X isI, Br, Cl or OTf with a to tributyl(vinyl)tin reagent in the presence ofa suitable catalyst such as bis-(triphenylphosphin)-palladiumchloride,in a suitable solvent such as dimethylformamide (DMF) and if desirablein the presence of an additive such as tetraethylammonium chlorideprovides compounds of Formula X or XI. Further, reaction of a compoundof Formula VII or IX, wherein X is I or Br, may be reacted with an aminein the presence of a suitable catalyst such as Cu(I)I and a suitablebase such as caesium carbonate and a suitable promotor such as L-prolineprovides a compound of Formula X or XI.

In an inversed fashion compounds of formula VII or IX (X: I, Br, Cl,OTf) can be converted into the corresponding boronic acid derivativesVIIa or IXa, wherein R can be H or lower alkyl independently and theresidues R can form a ring. For example, VII or IX can be reacted withbis-pinacolato-diboron in the presence of a suitable catalyst such as1,1-bis(di-tert-butylphosphino)ferrocene palladium dichloride and asuitable base such as potassium acetate or sodium, potassium or cesiumcarbonate or phosphate, in a suitable solvent such as dioxan,dimethylformamide (DMF), or dichloromethane (DCM) to yield the boronicesters VIIa or IXa, respectively. These can be reacted with appropriatearomatic halides in analogy as above to yield the desired couplingproducts of formula X or XI.

Further, as illustrated in Scheme 2, reaction of a compound of FormulaVII or IX, wherein X is N₃ with an alkyne in the presence of a suitablecatalyst such as copper(II)sulfate pentahydrate and a suitable reducingagent such as L-ascorbic acid in a suitable solvent such as dimethylsulfoxide (DMSO)/water provides a compound of Formula X or XI.

Further modifications of compounds of Formula X, XI and I by methodsknown in the art and illustrated in the Examples below, may be used toprepare additional compounds of the invention.

Dehydration of an amide of Formula XI to the corresponding nitrile ofFormula X may be carried out by use of a dehydration agent such as(methoxycarbonylsulfamoyl)triethyl ammonium hydroxide, in a suitablesolvent such as DCM.

As illustrated in Scheme 3, (transition) metal catalyzed reaction of acompound of Formula IV wherein X is I, Br, cl or OTf provides a compoundof Formula XII. For example, reaction with a boronic acid or thecorresponding boronic acid ester, in a suitable solvent such asacetonitrile, in the presence of a suitable catalyst such as1,1-bis(di-tert-butylphosphino)ferrocene palladium dichloride and asuitable base such as K₂CO₃ provides a compound of Formula XII.

An acid of Formula VI using standard literature procedures for theformation of an amide, for example in the presence of a base such asDIPEA and an activating agent such as HATU or TBTU, can be reacted withan amine of Formula XII in a suitable solvent. Standard peptide couplingreactions known in the art (see for example M. Bodanszky, 1984, ThePractice of Peptide Synthesis, Springer-Verlag) may be employed in thesesyntheses. Deprotection of functional groups is described in ‘ProtectiveGroups in Organic Synthesis’, T. W. Greene and P. G. M. Wuts,Wiley-Interscience. For example, for the deprotection oftert-butoxycarbonyl, an acid such as formic acid, p-toluenesulfonicacid, trifluoroacetic acid or HCl may be used in a suitable solvent suchas water, DCM or dioxane and can be performed on the crude amidecoupling product to provide a compound of Formula I. Another method todeprotect tert-butoxycarbonyl is the reaction with trimethyliodosilaneor trimethylchlorosilane in combination with sodium iodide in anappropriate solvent like acetonitrile, DMF or DCM.

SYNTHETIC EXAMPLES

The following are representative compounds of the invention which can bemade by the general synthetic schemes, the examples, and known methodsin the art. Starting materials and intermediates were eithercommercially available and purchased from catalogues of ABCR, ACROS,ACTIVATE, AK SCIENTIFIC LABS, ALDRICH, ALFA, ALLICHEM, APOLLO,ARKPHARMINC, AROMACIRCLE, BACHEM, COMBI-BLOCKS, COMBI-PHOS, ENAMINE,FLUKA, FRONTIER SCIENTIFIC, J. T BAKER, MERCACHEM, MERCK, NETCHEM,RIEDEL DE HAEN or were synthesized according to literature or asdescribed below in “Synthesis of starting materials/educts” Liquidchromatography-mass spectroscopy (LCMS) retention time and observed m/zdata for the compounds below are obtained by one of the followingmethods:

LC-MS Method 001_CA04 Device-Description Agilent 1100 with DAD, CTCAutosampler and Waters MSD Column Waters XBridge C18 Column Dimension4.6 × 30 mm Particle Size 3.5 μm Gradient/Solvent % Sol [H2O % Sol FlowTemp Time [min] 0.1% NH4OH] [Methanol] [ml/min] [° C.] 0.0 80.0 20.0 2.060.0 1.7 0.0 100.0 2.0 60.0 2.5 0.0 100.0 2.0 60.0

LC-MS Method 004_CA01 Device-Description Agilent 1100 with DAD, WatersAutosampler and MSD Column Waters Sunfire C18 Column Dimension 4.6 × 30mm Particle Size 3.5 μm Solvent Gradient % Sol [H₂O % Sol Flow Temp time[mm] 0.1% TFA] [Acetonitril] [ml/min] [° C.] 0.0 98.0  2.0 2.5 60.0 1.5 0.0 100.0 2.5 60.0 1.8  0.0 100.0 2.5 60.0

LC-MS Method V001_003 Device-Description Waters Alliance with DAD andMSD Column Waters XBridge C18 Column Dimension 4.6 × 30 mm Particle Size3.5 μm Gradient/Solvent % Sol [H2O, % Sol Flow Temp Time [mm] 0.1% TFA][Methanol] [ml/min] [° C.] 0.0 95 5 4 60 0.20 95 5 4 60 1.5 0 100 4 601.75 0 100 4 60

LC-MS Method V001_007 Device-Description Waters Alliance with DAD andMSD Column Waters XBridge C18 Column Dimension 4.6 × 30 mm Particle Size3.5 μm Gradient/Solvent % Sol [H2O, % Sol Flow Temp Time [mm] 0.1% TFA][Methanol] [ml/min] [° C.] 0.0 95 5 4 60 1.6 0 100 4 60 1.85 0 100 4 601.9 95 5 4 60

LC-MS Method V002_005 Device-Description Waters Alliance with DAD andMSD Column Waters Sunfire C18 Column Dimension 4.6 × 30 mm Particle Size3.5 μm Gradient/Solvent % Sol [H2O, % Sol Flow Temp Time [mm] 0.1% TFA][Methanol] [ml/min] [° C.] 0.0 95 5 4 60 1.6 0 100 4 60 1.85 0 100 4 601.9 95 5 4 60

LC-MS Method V003_003 Device-Description Waters Alliance with DAD andMSD Column Waters XBridge C18 Column Dimension 4.6 × 30 mm Particle Size3.5 μm Solvent Gradient % Sol [H₂O, % Sol Flow Temp time [min] 0.1% NH₃][Acetonitril] [ml/min] [° C.] 0.0 95 5 4 60 0.2 95 5 4 60 1.5 0 100.0 460 1.75 0 100 4 60

LC-MS Method V011_S01 Device-Description Waters Alliance with DAD andMSD Column Waters XBridge C18 Device-Description Waters Alliance withDAD and MSD Column Dimension 4.6 × 30 mm Particle Size 3.5 μm SolventGradient % Sol [H₂O, % Sol Flow Temp time [min] 0.1% NH₃] [Acetonitril][ml/min] [° C.] 0.0 97  3 5 60 0.2 97  3 5 60 1.6  0 100 5 60 1.7  0 1005 60

LC-MS Method V012_S01 Device-Description Waters Alliance with DAD andMSD Column Waters XBridge C18 Column Dimension 4.6 × 30 mm Particle Size3.5 μm Solvent Gradient % Sol [H₂O, % Sol Flow Temp time [min] 0.1% TFA][Acetonitril] [ml/min] [° C.] 0.0 97 3 5 60 0.2 97 3 5 60 1.6 0 100 5 601.7 0 100 5 60

LC-MS Method V018_S01 Device-Description Waters Alliance with DAD andMSD Column Waters Sunfire C18 Column Dimension 4.6 × 30 mm Particle Size3.5 μm Solvent Gradient % Sol % Sol Flow Temp time [min] [H₂O, 0.1% TFA][Acetonitril] [ml/min] [° C.] 0.0 97 3 5 60 0.2 97 3 5 60 1.6 0 100 5 601.7 0 100 5 60

LC-MS Method W018_S01 Device Description Waters 1525 with DAD and MSDColumn: Waters Sunfire C18 Column Dimension 4.6 × 30 mm Particle Size2.5 μm Gradient/Solvent % Sol % Sol Flow Temp Time [min] [H2O, 0.1% TFA][ACN] [ml/min] [° C.] 0.0 97 3 4 60 0.15 97 3 3 60 2.15 0 100 3 60 2.200 100 4,5 60 2.40 0 100 4,5 60

LC-MS Method X001_004 Device-Description Waters Acquity with DAD and MSDColumn Waters XBridge C18 Column Dimension 2.1 × 20 mm Particle Size 2.5μm Gradient/Solvent % Sol % Sol Flow Temp Time [min] [H₂O, 0.10% TFA][Methanol] [ml/min] [° C.] 0.0 95 5 1.4 60 0.05 95 5 1.4 60 1.00 0 1001.4 60 1.1 0 100 1.4 60

LC-MS Method X012_S01 Device-Description Waters Acquity with DAD and MSDColumn Waters XBridge BEH C18 Column Dimension 2.1 × 30 mm Particle Size1.7 μm Solvent Gradient % Sol % Sol Flow Temp time [min] [H₂O, 0.1% TFA][Acetonitril] [ml/min] [° C.] 0.0 99 1 1.6 60 0.02 99 1 1.6 60 1.00 0100 1.6 60 1.10 0 100 1.6 60

LC-MS Method X018_S01 Device-Description WatersAcquity with DAD and MSDColumn Waters Sunfire C18 Column Dimension 2.1 × 30 mm Particle Size 2.5μm Gradient/Solvent % Sol % Sol Flow Temp Time [min] [H₂O, 0.1% TFA][Acetonitril] [ml/min] [° C.] 0.0 99 1 1.5 60 0.02 99 1 1.5 60 1.00 0100 1.5 60 1.10 0 100 1.5 60

LC-MS Method Z002_005 Device Description Agilent 1200 with DAD and MSDColumn. Waters Sunfire C18 Column Ihmension 3 × 30 mm Particle Size 2.5μm Gradient/Solvent % Sol % Sol Flow Temp Time [min] [H2O, 0.1% TFA][Methanol] [ml/min] [° C.] 0.0 95 5 1.8 60 0.25 95 5 1.8 60 1.70 0 1001.8 60 1.75 0 100 2.5 60 1.90 0 100 2.5 60

LC-MS Method Z011_S03 Device-Description Agilent 1200 with DAD and MSDColumn Waters XBridge C18 Column Dimension 3 × 30 mm Particle Size 2.5μm Gradient/Solvent % Sol % Sol Flow Temp Time [min] [H₂O, 0.1% NH3][Acetonitril] [ml/min] [° C.] 0.00 97 3 2.2 60 0.20 97 3 2.2 60 1.20 0100 2.2 60 1.25 0 100 3 60 1.40 0 100 3 60

LC-MS Method Z012_S04 Device-Description Agilent 1200 with DAD and MSDColumn Waters XBridge C18 Column Dimension 3 × 30 mm Particle Size 2.5μm Solvent Gradient % Sol % Sol Flow Temp time [min] [H₂O, 0.1% TFA][Acetonitril] [ml/min] [° C.] 0.00 97 3 2.2 60 0.20 97 3 2.2 60 1.20 0100 2.2 60 1.25 0 100 3 60 1.40 0 100 3 60

LC-MS Method Z018_S04 Device-Description Agilent 1200 with DAD and MSDColumn Waters Sunfire C18 Column Dimension 3 × 30 mm Particle Size 2.5μm Solvent Gradient % Sol % Sol Flow Temp time [min] [H₂O, 0.1% TFA][Acetonitril] [ml/min] [° C.] 0.00 97 3 2.2 60 0.20 97 3 2.2 60 1.20 0100 2.2 60 1.25 0 100 3 60 1.40 0 100 3 60

Synthesis of(2S)—N-[(1S)-1-cyano-2-[4-(4-cyano-3-methylsulfonyl-phenyl)-2-fluoro-phenyl]ethyl]-3-azabicyclo[2.2.2]octane-2-carboxamideExample 1

Step 1: Synthesis of Intermediate I-1.1

R1 (20.0 g, 55.4 mmol) is suspended in DCM (400 mL) and R2 (26.4 g,110.9 mmol) is added. The reaction mixture is stirred for 12 h underargon atmosphere. Afterwards the reaction mixture is washed with water.The organic layer is dried over MgSO₄, filtrated and the filtrate isconcentrated. The residue is dissolved in DCM, filtrated by flashchromatography (using solvent mixture cyclohexane/ethyl acetate=70/30)and the filtrate is concentrated. Yield 97% m/z 287/343 [M+H]+, rt 1.29min, LC-MS Method X012_S01.

The following intermediates as shown in Table 2 are synthesized in asimilar fashion from the appropriate intermediate or by directboronylation of Intermediate I-1.1:

TABLE 2 m/z rt Intermediate Structure [M + H]+ (min) LC-MS methodI-1.1.1

395 [M + Na]+ 1.43 V001_007 I-1.1.2

391 1.29 V012_S01 I-1.1.3

391 1.36 V012_S01

Step 1a: Synthesis of Intermediate I-1.1.3

Intermediate I-1.1 (5.8 g, 16.9 mmol), bis-pinacolato-diboron (5.2 g,20.28 mmol), potassium acetate (4.976 g, 50.7 mmol) andBis(diphenylphosphino)ferrocene]dichloropalladium(II) (PdCl2(dppf)) asDCM complex (1.38 g, 1.69 mmol) are suspended in dioxane under argon andis stirred for 2 h at 80° C. After cooling the mixture is treated withDCM and filtered. The filtrate is washed with water and dried overMgSO₄. After filtration the solution is evaporated in vacuo. The residueis dissolved in DCM and purified by MPLC (cyclohexane/ethyl acetate 8:2,wave length 230 nm). The fractions containing the product are combinedand evaporated in vacuo. Yield 97% m/z 391 [M+H]+, rt 1.36 min, LC-MSMethod V012_S01.

Step 2: Synthesis of Intermediate I-1.2

To I-1.1 (3.00 g, 8.74 mmol) in acetonitrile (50 mL) R3 (2.82 g, 9.18mmol) and potassium phosphate solution (2 mol/L, 8.74 mL) are added. Themixture is purged with argon,[1,1′-Bis(di-tert-butylphosphino)ferrocene]palladium dichloride (0.57 g,0.87 mmol) is added to and then the reaction mixture is heated to 80° C.for 2.5 h. Ethyl acetate and half saturated brine are added to thereaction mixture. The organic layer is dried over MgSO₄ andconcentrated. Yield 97% m/z 461/444 [M+NH4]+/[M+H]+, rt 1.12 min, LC-MSMethod V011_S01.

The following intermediates as shown in Table 3 are synthesized in asimilar fashion from the is appropriate intermediate:

TABLE 3 m/z rt LC-MS Intermediate Educt Structure of Intermediate [M +H]+ (min) method I-1.2.1 I-1.1.3

396 0.96 V012_S01 I-1.2.2 I-1.1.1

392 1.36 V001_007 I-1.2.3 I-1.1.2

444 1.21 V018_S01 I-1.2.4 I-1.1.3

446 1.18 V012_S01

During the synthesis of intermediates I-1.2.1 and I-1.2.4 the bromide(I-1.1) is transformed into the corresponding dioxaborolane compound: ToI-1.1 (5.80 g, 17 mmol) in anhydrous dioxane (60 mL)Bis(pinacolato)diboron (5.20 g, 20 mmol) and potassium acetate (4.98 g,51 mmol) are added. The mixture is purged with argon,[1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (1.38 g, 1.7mmol) is added to the mixture and heated to 80° C. for 2 h. DCM is addedand the mixture is filtrated. The filtrate is diluted with water andextracted with DCM. The organic layer is dried over MgSO₄, filtrated andconcentrated. The residue is purified by flash chromatography(cyclohexane/ethyl acetate=8/2) and concentrated. Yield 97% m/z291/335/391 [M+H]+, rt 1.36 min, LC-MS Method V012_S01.

And for the synthesis of I-1.2.1 an aq. solution of sodium carbonate (2mol/L) is used instead of the potassium phosphate solution.

Step 3: Synthesis of Intermediate I-1.3

I-1.2 (4.85 g, 10.9 mmol) is dissolved in formic acid. The mixture isheated to 50° C. for 25 min in a pressure vessel. The reaction mixtureis dropped carefully in saturated NaHCO₃ solution and then extractedthree times with ethyl acetate. The organic layer is dried over MgSO₄,filtrated and then to concentrated. The residue is purified by flashchromatography (DCM/methanol=98/2). Yield 28%. m/z 344/361[M+H]+/[M+NH₄]+, rt 0.85 min, LC-MS Method VO11_S01.

The following intermediates as shown in Table 4 are synthesized in asimilar fashion from the appropriate intermediate:

TABLE 4 m/z rt LC-MS Intermediate Educt Structure of Intermediate [M +H]+ (min) method I-1.3.1 I-1.2.1

396 0.96 V012_S01 I-1.3.2 I-1.2.2

292 n.d. n.d. I-1.3.3 I-1.2.3

344 0.76 V018_S01 I-1.3.4 I-1.2.4

346 0.96 V011_S01

During the synthesis of intermediates I-1.3.1, I-1.3.2, I-1.3.3 andI-1.3.4 p-toluenesulfonic acid monohydrated in acetonitrile is added tothe educt and the reaction mixture is stirred for 12 h.

Step 4: Synthesis of Intermediate I-1.4

To R4 (50 mg, 0.20 mmol) in DMF (1.5 mL) HATU (82 mg, 0.22 mmol) anddiisopropylethylamine (135 μL, 0.78 mmol) are added and the reactionmixture is stirred for 15 min. Then intermediate I-1.3 (71 mg, 0.21mmol) is added and the mixture is stirred for additional 12 h. Thereaction solution is directly purified by reversed phase HPLC. Yield75%, m/z 581/525/481 [M+H]+, rt 1.17 min, LC-MS Method V011_S01.

The following intermediates as shown in Table 5 are synthesized in asimilar fashion from the appropriate intermediate:

TABLE 5 m/z rt LC-MS Intermediate Educt Structure of Intermediate [M +H]+ (min) method I-1.4.1 I-1.3.1

433/477/533 1.32 V011_S01 I-1.4.2 I-1.3.2

529 1.46 V002_005 I-1.4.3 I-1.3.3

581 1.25 V018_S01 I-1.4.4 I-1.3.4

583 1.27 V011_S01

During the synthesis of intermediates I-1.4.2 TBTU is used instead ofHATU.

Step 5: Synthesis of Example 1

I-1.4 (85 mg, 0.15 mmol) is dissolved in formic acid. The mixture isheated to 50° C. for 15 min in a pressure vessel. The product ispurified by reversed phase HPLC. Yield 79%, m/z 481 [M+H]+, rt 108 min,LC-MS Method V011_S01.

Method B Synthesis of(2S)—N-[(1S)-cyano-2-[4-(2-oxoindolin-6-yl)phenyl]ethyl]-3-azabicyclo[2.2.2]octane-2-carboxamideExample 2

Step 1: Synthesis of Intermediate I-2.1

R4 (1.62 g, 6.16 mmol) is dissolved in DCM (60 mL) and the mixture ispurged with argon. Then 1.5 equivalents diisopropylethylamine (1.45 mL,8.40 mmol) and HATU (2.34 g, 6.16 mmol) are added and the mixture isstirred for 30 min. R5 (2.00 g, 5.60 mmol) and additional 1.5 equivalentdiisopropylethylamine (1.45 mL, 8.40 mmol) are added and the reactionmixture is stirred for 12 h. To the resulting mixture water is added andthe DCM phase is extracted 3 times with water. The to organic layer iswashed with brine and concentrated. The crude product is purified byHPLC. Yield 67%, m/z 480 [M+H]+, rt 0.95 min, LC-MS Method Z018_S04.

Step 2: Synthesis of Intermediate I-2.2

I-2.1 (1.95 g, 4.06 mmol) is stirred in anhydrous DCM (30 mL) underargon for 15 min. Afterwards R2 (1.94 g, 8.13 mmol) is added and thereaction mixture is stirred for 12 h under argon. Because educt I-2.1 isstill remaining, additional 1.5 eq educt R2 are added and the solutionis stirred for additional 3 h. DCM and 2 M Na₂CO₃ solution are added tothe reaction mixture. The organic layer is extracted two times withNa₂CO₃ solution (2 mol/L) and two times with tartaric acid (10%). Thecombined organic layers are dried over MgSO₄ and concentrated. Theproduct is dissolved in water/acetonitrile and freeze-dried. Yield 97%m/z 462/406/362 [M+H]+, rt 1.04 min, LC-MS Method Z018_S04.

Step 3: Synthesis of Intermediate I-2.3

R6 (34 mg, 0.13 mmol) and I-2.2 (46 mg, 0.10 mmol) are put together invented acetonitrile (3 mL) and then aq. potassium carbonate solution (2mol/L, 100 μL) is added. Then 1,1-Bis(di-tert-butylphosphino)ferrocenepalladium dichloride (7 mg, 0.01 mmol) is added quickly and the reactionvessel is purged with argon. The reaction mixture is heated to 80° C.for 2 h. Further 0.5 eq of educt R6 and further 0.1 eq of the catalystare added and the reaction mixture is stirred at 80° C. for additional12 h. The resulting mixture is filtrated over a mixture of basicaluminium oxide and silica gel 1/1. The residue is purified by reversedphase HPLC. Yield 41% m/z 514 [M+H]+, rt 0.92 min, LC-MS MethodZ018_S04.

The following intermediates as shown in Table 6 are synthesized in asimilar fashion from the appropriate intermediate:

TABLE 6 m/z rt LC-MS Intermediate Structure [M + H]+ (min) methodI-2.3.1

429 (M-BOC) + H+ 0.92 Z011_S03 I-2.3.2

563 0.91 Z011_S03 I-2.3.3

485 1.24 001_CA04 I-2.3.4

538 0.82 Z018_S04 I-2.3.5

515 0.88 Z018_S04 I-2.3.6

553 1.06 001_CA04 I-2.3.7

539 1.08 001_CA04 I-2.3.8

515 0.91 Z018_S04 I-2.3.9

538 0.83 Z018_S04 I-2.3.10

503 0.84 Z011_S03 I-2.3.11

553 1.01 001_CA04 I-2.3.12

503 1.01 001_CA04 I-2.3.13

529 0.97 Z018_S04 I-2.3.14

529 1.07 001_CA04 I-2.3.15

573 0.76 Z018_S04 I-2.3.16

552 1.20 001_CA04 I-2.3.17

514 1.43 001_CA04 I-2.3.18

486 1.19 001_CA04

Step 4: Synthesis of Example 2

To I-2.3 (31 mg, 0.06 mmol) in acetonitrile (1 mL) p-toluenesulfonicacid monohydrate (34 mg, 0.18 mmol) is added and the mixture is stirredfor 12 h. The reaction mixture is diluted with DMF and directly purifiedby reversed phase HPLC. Yield 45%, m/z 415 [M+H]+, rt 0.66 min, LC-MSMethod Z018_S04.

Method C Synthesis of(2S)—N-[(1S)-1-cyano-2-[4-(4-cyano-3-fluoro-phenyl)phenyl]ethyl]-3-azabicyclo[2.2.2]octane-2-carboxamideExample 7

Step 1: Synthesis of Intermediate I-3.1

To R4 (200 mg, 0.78 mmol) in DMF (5 mL) is added TBTU (290.48 mg, 0.91mmol) and DIPEA (0.26 mL, 1.51 mmol). R18 (200 mg, 0.75 mmol) is addedand stirred for 3 h at r.t. Potassium carbonate is added and thereaction mixture is filtered over basic alox. The residue is purifiedover silica gel (cyclohexane/ethyl acetate 100:0-50:50) to give theintermediate I-3.1. Yield 45%.

Step 2: Synthesis of Example 7

I-3.1 (170 mg, 0.34 mmol) and formic acid (1 mL) is stirred 2 h at r.t.The reaction mixture is diluted with methanol and purified by reversedphase HPLC.

Yield 23% m/z 403 [M+H]+, rt 1.15 min, LC-MS Method V002_(—)005.

Synthesis of Starting Materials/Educts Amino Acids Synthesis oftert-butylN-[(1S)-2-amino-1-[(4-bromo-2-fluoro-phenyl)methyl]-2-oxo-ethyl]carbamate(R1)

Step 1: Synthesis of Intermediate I-4.1

R8 (212 g, 1151 mmol) in tetrahydrofuran (dry) (600 mL) is cooled to−78° C. Then n-butyllithium (2.5 M in hexanes, 552 mL, 1381 mmol) isadded dropwise, keeping the temperature below −78° C. After 30 min R9(324 g, 1209 mmol) in tertahydrofuran (dry) (120 mL) is added dropwise.The reaction mixture is stirred at −78° C. for 1 h. The mixture isquenched with saturated NH₄Cl solution and extracted three times withethyl acetate. The organic layer is washed with brine, dried over Na₂SO₄and evaporated in vacuo. The residue is purified by flash chromatography(heptane/ethyl acetate=80/20). Yield 60%.

Step 2: Synthesis of Intermediate I-4.2

To I-11.1 (104 g, 265 mmol) in acetonitrile (600 mL) aq. 0.2 M HCl (2788mL, 558 mmol) is added.

The mixture is stirred at RT for 12 h. The mixture is extracted withdiethylether and the pH of the aq. layer is adjusted to ˜8 with sat.NaHCO₃-solution. Then it is extracted three times with ethyl acetate.The organic layer is washed with brine, dried over Na₂SO₄ andconcentrated. Yield 80%.

Step 3: Synthesis of Intermediate I-4.3

I-11.2 (62.4 g, 211 mmol) is stirred in aq. 3 M HCl (3 mol/L, 1000 mL)at 60° C. for 16 h. The mixture is cooled down and the pH is adjusted to˜7 with aq. 6 M NaOH. Then the reaction mixture is filtered, washedthree times with water and dried in a vacuum oven at 40° C. for 12 h.Yield 74%.

Step 4: Synthesis of Intermediate I-4.4

To I-11.3 (151 g, 546 mmol) in 1,4-dioxane (2.2 L) is added aq. 2 Msodium carbonate (301 mL) and di-tertbutyl dicarbonate (138 g, 147 mL).The mixture is stirred for 4 h. Then water is added and the pH isadjusted to ˜4-5 with citric acid. The mixture is extracted three timeswith ethyl acetate. The organic layer is washed with brine, dried overNa₂SO₄ and concentrated. The residue is stirred in heptane for 15 minand the product is filtered off. Yield 87%.

The following intermediate as shown in Table 8.1 is synthesized in asimilar fashion from the appropriate intermediate:

TABLE 8.1 Inter- m/z rt LC-MS mediate Structure [M + H]+ (min) methodI-4.4.1

410 1.21 V012_S01

Step 5: Synthesis of R1

To I-11.4 (181 g, 476 mmol) in dry DMF (1200 mL) N-methylmorpholine (72g, 713 mmol) and TBTU (153 g, 476 mmol) are added and the reactionmixture is stirred for 30 min. Then the reaction mixture is cooled to 0°C. and aq. 35% ammonium solution (47 mL, 856 mmol) is added and themixture is stirred at room temperature for 12 h. Water is added and theformed product is filtered off and washed three times with water. Theproduct is dried in a vacuum oven at 40° C. for 72 h. Yield 64%.

The following intermediates as shown in Table 8.2 are synthesized in asimilar fashion from the appropriate intermediate:

TABLE 8.2 m/z rt LC-MS Intermediate Structure [M + H]+ (min) method R1.1

391 1.10 V011_S01 R1.2

343 1.39 Z002_005 R1.3

409 1.05 V011_S01

Synthesis of4-[4-[(2S)-2-amino-2-cyano-ethyl]phenyl]-2-fluoro-benzonitrile (R18)

Step 1: Synthesis of Intermediate I-8.1

To 4-cyano-3-fluoroboronic acid (0.16 g, 0.97 mmol) in dioxane (10 mL)is added I-1.1.1 (0.3 g, 0.81 mmol) andBis(bis(1,2-diphenylphosphino)ethane)palladium(0) (10 mg, 0.01 mmol) anddegassed with nitrogen for 15 min. A solution of potassium carbonate(0.23 g, 1.63 mmol) in water (1 mL) is added and again degassed for 15min. The reaction mixture is stirred at 80° C. overnight and afterwardsconcentrated in vacuo. The crude residue is diluted with ethyl acetateand extracted with water and brine, dried over sodium sulfate andconcentrated. The crude product is purified over column chromatography(ethyl acetate/hexane 1:4). Yield: 54%.

Step 2: Synthesis of R18

I-8.1 (0.16 g, 0.44 mmol) is dissolved in formic acid (2 mL) and stirredat 50° C. for 20 min. The reaction mixture is concentrated in vacuo andthe residue is purified over column chromatography(dichloromethane/methanol 98:2). Yield: 52%.

Synthesis of (2S)-2-amino-3-(4-bromophenyl)propanamide (R5)

To R1.2 (2.00 g, 5.8 mmol) in DCM (12 mL) TFA (4 mL) is added and thereaction mixture is stirred for 3 h. Then the reaction mixture isconcentrated, the residue is dissolved in DCM and water. The solution isfreeze-dried. Yield >95% m/z 243 [M+H]+, rt 0.52 min, LC-MS MethodZ018_S04.

Amines Synthesis of(2S)-3-tert-butoxycarbonyl-3-azabicyclo[2.2.2]octane-2-carboxylic acid(R4)

Step 1: Synthesis of Intermediate I-6.1

To R13 (1.00 g, 4.6 mmol) in THF (20 mL) are added 1 M NaOH (10 mL, 10.0mmol) and di-tert-butyldicarbonat (1.19 g, 5.5 mmol) and the reactionmixture is stirred at 70° C. for 12 h. The pH is adjusted to 4 with 1 MHCl. The mixture is extracted with DCM. The organic layer is dried overMgSO₄ and concentrated. Yield >95%, m/z 284 [M+H]+, rt 0.78 min, LC-MSMethod X001_(—)004.

Step 2: Synthesis of R4

To I-6.1 (3.50 g, 12.4 mmol) in dioxane (30 mL) is added LiOH (0.44 g,18.5 mmol)—dissolved in 6 mL water—dropwise. The reaction mixture isheated to 60° C. for 12 h. Additional 3.5 eq LiOH are added and themixture is heated to 60° C. for additional 24 h. The reaction mixture isextracted with water and DCM. The aq. layer is acidified with HCl andextracted three times with DCM. The organic layer is dried over MgSO₄and concentrated. Yield >95%, m/z 256 [M+H]+, rt 0.82 min, LC-MS MethodZ018_S04.

Halogenides Synthesis of 5-bromo-2-methyl-isoindoline (R15)

The pH of a mixture of R14 (1.85 g, 7.9 mmol) in methanol (100 mL) andwater (10 mL) is adjusted to ˜5 with acetic acid. Then a 37% formalinsolution (1.28 mL, 15.8 mmol) is added and the mixture is stirred for 15min. Sodium cyanoborohydride (0.74 g, 11.8 mmol) is added and thereaction mixture is stirred for additional 12 h. The mixture isconcentrated and ethyl acetate and aq. 1 M NaOH solution is added to theresidue. The organic layer is washed with NaCl solution, dried overMgSO₄ and concentrated. The residue is dissolved in diethyl ether andethereal HCl is added dropwise. The resulting precipitation is filteredoff. Yield 62% m/z 212/214 [M+H]+, rt 0.65 min, LC-MS Method V012_S01.

Synthesis of 5-bromo-2-methylsulfonyl-benzonitrile (R17)

Step 1: Synthesis of Intermediate I-7.1

To 5-Bromo-2-fluoro-benzonitrile (10.05 g, 50.25 mmol) in DMSO (30 mL)is added to sodiummethanethiolate (3.87 g, 55.27 mmol) portionwise at 0°C. The reaction mixture is stirred for 2 h at r.t. Sodiummethanethiolate(1.06 g, 15.07 mmol) is added and stirred for further 2 h at r.t. Thereaction mixture is diluted with water (100 mL) and the precipitate isfiltered off and dried in vacuo at 50° C.

Yield 88% m/z 228/230 [M+H]+, rt 1.26 min, LC-MS Method V018_S01.

Step 2: Synthesis of R17

To I-7.1 (10.10 g, 44.28 mmol) in dichloromethane is added3-chloroperoxybenzoic acid (19.85 g, 88.55 mmol) at 0° C. and stirredovernight at r.t. 3-chloroperoxybenzoic acid (3.97 g, 17.71 mmol) isadded and stirred again overnight at r.t. The precipitate is filteredoff and the filtrate is extracted with saturated sodiumhydrogencarbonate solution. The aq. layer is washed withdichloromethane. The organic layers are combined, dried over MgSO₄ andconcentrated. Yield 97% m/z 277/279 [M+H]+, rt 0.88 min, LC-MS MethodV011_S01.

Boronic Acids or Esters Synthesis of1-Methyl-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1,3-dihydro-indol-2-one(R12

Step 1: Synthesis of Intermediate I-5.1

To R10 (25.0 g, 111 mmol) in acetonitrile (750 mL) is added MeI (15 mL,241 mmol) and K₂CO₃ (60.0 g, 434 mmol) and the reaction mixture isstirred at 60° C. for 2 h. The reaction mixture is filtered andconcentrated. Water and ethyl acetate are added to the residue. Theorganic layer is extracted twice with water, is dried over MgSO₄ andconcentrated. Yield 56%, m/z 240/242 [M+H]+, rt 0.48 min, LC-MS MethodX001_(—)004.

The following intermediates as shown in Table 9 are synthesized in asimilar fashion from the appropriate intermediate:

TABLE 9 LC- Inter- m/z rt MS mediate Structure [M + H]+ (min) methodI-5.1.1

284/286 1.12 V003_ 003 I-5.1.2

240/242 0.49 X001_ 004

Step 2: Synthesis of Intermediate I-5.2

I-5.1 (15.0 g, 63 mmol) and hydrazine hydrate (30 mL, 618 mmol) areheated to 125° C. for 72 h. To the cool reaction mixture DCM is addedand extracted with water and 1 M HCl. The organic layer is dried overMgSO₄ and concentrated. The crystallized residue is dissolved in DCM,methanol is added and the DCM is removed under vacuum. The crystallizedproduct is filtered with sunction and washed with cold methanol. Yield63%, m/z 226/228 [M+H]+, rt 1.16 min, LC-MS Method V001_(—)003.

The following intermediate as shown in Table 10 is synthesized in asimilar fashion from the appropriate intermediate:

TABLE 10 LC- Inter- m/z rt MS mediate Structure [M + H]+ (min) methodI-5.2.1

270 0.83 Z018_ S04 1-5.2.2

226 0.80 Z018_ S04

Step 3: Synthesis of Intermediate R12

To I-5.2 (32.0 g, 142 mmol) in anhydrous dioxane (400 mL) is added R11(54.4 g, 241 mmol) and potassium acetate (41.6 g, 424 mmol). The mixtureis purged with Argon,[1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) as a complexwith dichloromethane (11.2 g, 14 mmol) is added and the mixture isheated to 90° C. for 2 h. The reaction mixture is diluted with ethylacetate and water, the organic layer is washed with water, dried overMgSO₄ and concentrated. The residue is purified via flash chromatography(cyclohexane/EA=70:30). Yield 72%, m/z 274 [M+H]+, rt 0.67 min, LC-MSMethod V011_S01.

The following intermediates as shown in Table 1 are synthesized in asimilar fashion from the appropriate intermediate:

TABLE 11 m/z rt LC-MS Intermediate Structure [M + H]+ (min) method R3

325 [M + NH₄]+ 0.30 X018_S01 R12.1

226 (boronic acid) 0.66 V018_S01 R12.2

192 0.91 Z018_S04 R12.3

318 0.55 Z018_S04 R12.4

274 0.91 Z018_S04

EXAMPLES

(rt=retention time) Deprotection Methods: TSA (toluene sulfonic acid cf.Example 2), SI (trimethylsilyl iodide cf. example 3), FA (formic acidcf. example 1), TFA (trifluoroacetic acid).

TABLE 12 Syn./Deprot. Yield Example Structure Educt Method [%] 1

I-1.4 A/FA 79 2

I-2.3 B/TSA 45 4

I-1.4.2 A/FA 33 6

I-2.3.1 B/TSA 53 7

I-3.1. C/FA 23 8

I-2.3.2 B/TSA 83 9

I-2.3.3 B/FA 90 10

I-2.3.4 B/TSA 81 11

I-2.3.5 B/TSA 81 12

I-2.3.6 B/TSA 85 13

I-2.3.7 B/FA 54 14

I-2.3.8 B/TSA 75 15

I-2.3.9 B/FA 84 16

I-2.3.10 B/TSA 100 17

I-2.3.11 B/TSA 37 18

I-2.3.12 B/TSA 66 19

I-2.3.13 B/TSA 65 20

I-2.3.14 B/TSA 69 21

I-2.3.15 B/FA 88 22

I-2.3.16 B/TSA 58 23

I-2.3.17 B/TSA 56 24

I-2.3.18 B/TSA 33 25

I-1.4.1 A/TSA 62 26

I-1.4.3 A/TSA 60 27

I-1.4.4 A/TSA 71

ANALYTICAL DATA OF EXAMPLES m/z rt Ex. [M + H]+ [min] LC-MS-Method 1 4811.08 V011_S01 2 415 0.66 Z018_S04 4 429 1.00 V002_005 6 429 0.57Z018_S04 7 403 1.15 V002_005 8 463 0.68 Z018_S04 9 385 1.31 W018_S01 10438 0.67 Z018_S04 11 415 1.31 Z018_S04 12 453 1.13 W018_S01 13 439 1.15W018_S01 14 415 0.65 Z018_S04 15 438 1.15 W018_S01 16 403 0.62 Z018_S0417 453 1.08 W018_S01 18 403 1.08 W018_S01 19 429 1.32 Z018_S04 20 4291.14 W018_S01 21 473 0.61 Z018_S04 22 452 1.27 W018_S01 23 414 1.50W018_S01 24 386 1.26 W018_S01 25 433 1.21 V011_S01 26 481 0.88 V018_S0127 483 1.07 V011_S01

ABBREVIATIONS

-   ACN acetonitrile-   ALOX aluminium oxide-   aq. aqueous-   BOC tert. butyloxycyrbonyle--   d day-   DCM dichloromethane-   DEA diethylamine-   DIPEA n,n-diisopropylethylamine-   DIPE diisopropyl ether-   DMAP 4-dimethylaminopyridine-   DMF n,n-dimethylformamide-   DMSO dimethyl sulfoxide-   EA ethyl acetate-   FA formic acid-   h hour-   HATU o-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium    hexafluoro-phosphate-   LiOH lithium hydroxide-   MeOH methanol-   MSA methanesulfonic acid-   MeTHF methyl tetrahydrofuran-   RT, r.t. room temperature-   rt retention time-   sat. saturated-   SI trimethylsilyl iodide-   TBME tert-butyl methyl ether-   TBTU o-(1H-benzo-1,2,3-triazol-1-yl)-N,N,N′,N′-tetramethyluronium    tetrafluoroborate-   TEA triethylamine-   TFA trifluoroacetic acid-   THF tetrahydrofuran-   TSA toluene sulfonic acid

Pharmacological Data

Other features and advantages of the present invention will becomeapparent from the following more detailed examples which illustrate, byway of example, the principles of the invention.

Inhibition of Human DPPI (Cathepsin C)

Materials: Microtiterplates (Optiplate-384 F) were purchased fromPerkinElmer (Prod. No. 6007270). The substrate Gly-Arg-AMC was fromBiotrend (Prod.-No. 808756 Custom peptide). Bovine serum albumin (BSA;Prod. No. A3059) and Dithiothreitol (DTT; Prod. No D0632) were fromSigma. TagZyme buffer was from Riedel-de-Haen (Prod.-No. 04269), NaClwas from Merck (Prod.-No. 1.06404.1000) and morpholinoethane sulfonicacid (MES), was from Serva (Prod.-No. 29834). The DPP1 inhibitorGly-Phe-DMK was purchased from MP Biomedicals (Prod.-No. 03DK00625). Therecombinant human DPPI was purchased from Prozymex. All other materialswere of highest grade commercially available.

The following buffers were used: MES buffer: 25 mM MES, 50 mM NaCl, 5 mMDTT, adjusted to pH 6.0, containing 0.1% BSA; TAGZyme Buffer: 20 mMNaH₂PO₄, 150 mM NaCl adjusted to pH 6.0 with HCl

Assay Conditions:

The recombinant human DPPI was diluted in TAGZyme buffer to 1 U/ml (38.1μg/ml, respectively), and then activated by mixing in a 1:2 ratio with aCysteamine aqueous solution (2 mM) and incubating for 5 min at roomtemperature.

Five uL test compound (final concentration 0.1 nM to 100 μM) in aquabidest (containing 4% DMSO, final DMSO concentration 1%) were mixed with10 μL of DPPI in MES buffer (final concentration 0.0125 ng/μL) andincubated for 10 min. Then, 5 μL of substrate in MES buffer (finalconcentration 50 μM) were added. The microtiter plates were thenincubated at room temperature for 30 min. Then, the reaction was stoppedby adding 10 μL of Gly-Phe-DMK in MES-buffer (final concentration 1 μM).The fluorescence in the wells was determined using a Molecular DevicesSpectraMax M5 Fluorescence Reader (Ex 360 nm, Em 460 nm) or an EnvisionFluorescence Reader (Ex 355 nm, Em 460 nm).

Each assay microtiter plate contained wells with vehicle controls (1%DMSO in bidest+0.075% BSA) as reference for non-inhibited enzymeactivity (100% Ctl; high values) and wells with inhibitor (Gly-Phe-DMK,in bidest+1% DMSO+0.075% BSA, final concentration 1 μM) as controls forbackground fluorescence (0% Ctl; low values).

The analysis of the data was performed by calculating the percentage offluorescence in the presence of test compound in comparison to thefluorescence of the vehicle control after subtracting the backgroundfluorescence using the following formula:(RFU(sample)−RFU(background))*100/(RFU(control)−RFU(background))

Data from these calculations were used to generate IC₅₀ values forinhibition of DPPI, respectively.

Inhibition of DPPI Ex. IC50 [μM] 1 0.0301 2 0.0501 4 0.0322 6 0.0522 70.0664 8 0.0702 9 0.0730 10 0.0735 11 0.0867 12 0.0974 13 0.1023 140.1028 15 0.1105 16 0.1180 17 0.1237 18 0.1307 19 0.1337 20 0.1367 210.1598 22 0.1644 23 0.2437 24 0.2485 25 0.0980 26 0.0278 27 0.0733Inhibition of Human Cathepsin K

Materials: Microtiterplates (Optiplate-384 F were purchased fromPerkinElmer (Prod. No. 6007270). The substrate Z-Gly-Pro-Arg-AMC wasfrom Biomol (Prod.-No. P-142). L-Cysteine (Prod. No. 168149) was fromSigma. Sodium actetate was from Merck (Prod.-No. 6268.0250), EDTA wasfrom Fluka (Prod.-No. 03680). The inhibitor E-64 was purchased fromSigma (Prod.-No. E3132). The recombinant human Cathepsin K proenzyme waspurchased from Biomol (Prod. No. SE-367). All other materials were ofhighest grade commercially available.

The following buffers were used: Activation buffer: 32.5 mM sodiumacetate, adjusted to pH 3.5 with HCl; Assay buffer: 150 mM sodiumacetate, 4 mM EDTA, 20 mM L-Cysteine, adjusted to pH 5.5 with HCl,

Assay Conditions:

To activate the proenzyme, 5 μl procathepsin K were mixed with 1 ulactivation buffer, and incubated at room temperature for 30 min.

5 μL test compound (final concentration 0.1 nM to 100 μM) in aqua bidest(containing 4% DMSO, final DMSO concentration 1%) were mixed with 10 uLof Cathepsin K in assay buffer (final concentration 2 ng/μL) andincubated for 10 min. Then 5 μL of substrate in assay buffer (finalconcentration 12.5 μM) were added. The plates were then incubated atroom temperature for is 60 min. Then, the reaction was stopped by adding10 μL of E64 in assay buffer (final concentration 1 μM). Thefluorescence in the wells was determined using a Molecular DevicesSpectraMax M5 Fluorescence Reader (Ex 360 nm, Em 460 nm).

Each assay microtiter plate contains wells with vehicle controls (1%DMSO in bidest) as reference for non-inhibited enzyme activity (100%Ctl; high values) and wells with inhibitor (E64 in bidest+1% DMSO, finalconcentration 1 μM) as controls for background fluorescence (0% Ctl; lowvalues). The analysis of the data was performed by calculating thepercentage of fluorescence in the presence of test compound incomparison to the fluorescence of the vehicle control after subtractingthe background fluorescence:(RFU(sample)−RFU(background))*100/(RFU(control)−RFU(background))

Data from these calculations were used to generate IC₅₀ values forinhibition of Cathepsin K, respectively.

Inhibition of Cathepsin K Ex. IC50 [μM] 1 2.7 2 4.2 4 6.3 7 5.7 8 5.3 914.8 10 5.3 11 11.0 12 9.9 13 10.8 17 6.7 18 9.7Determination of Neutrophil Elastase Activity in U937 Cytosolic LysatePreparation after Incubation with Test CompoundMaterials:Optiplate 384F were purchased from PerkinElmer (Prod. No. #6007270). 24well Nunclon cell culture plates (No. 142475) and 96 well plates (No.267245) were from Nunc. Dimethylsulfoxid (DMSO) was from Sigma (Prod.No. D8418). Nonidet-P40 (NP40) was from USBiological (Prod. No. N3500)Substrate, specific for Neutrophil elastase, was from Bachem(MeOSuc-Ala-Ala-Pro-Val-AMC; Prod. No. I-1270).Human neutrophil elastase was from Calbiochem (Prod. No. 324681)Buffers:Tris-buffer (100 mM Tris; 1M NaCL; pH 7.5)Tris-buffer+HSA 0.1%; Human Serum Albumin from Calbiochem (Cat#. 126658)Serine-protease buffer (20 mM Tris; 100 mM NaCL; pH 7.5)+0.1% HSASerine protease lysis buffer: 20 mM Tris-HCL; 100 mM NaCl pH 7.5; +0.2%Nonidet-P40;PBS: phosphate buffered saline, without Ca and Mg, from GibcoCell Culture:U937 from ECACC (Cat. No. 85011440) cultured in suspension at 37° C. and5% CO₂.Cell density: 0.2-1 Mio. Cells/ml.Medium: RPMI1640 GlutaMAX (No. 61870) with 10% FCS from GibcoCell Seeding and Treatment:Compounds in 100% DMSO were diluted in Medium (—FCS) with 10% DMSO andfurther diluted according to the experiment planned.20 μl of the compound solution was transferred in the respective wellsof the 24 well plate and diluted with 2 ml cell suspension/wellcontaining 1′105 cells/ml (final concentration of DMSO=0.1%). Compounddilution factor=100Compounds (up to 7 concentrations) were tested in triplicates with 3wells for the DMSO 0.1% control, incubated for 48 hours without mediumchange at 37° C., 5% CO2 and 95% relative to humidity.Cell Harvesting and Cell Lysate:

Transfer the cell suspension in 2.2 ml Eppendorf cups. Separate cellsfrom medium by centrifugation (400×g; 5 min; RT); discard thesupernatant. Resuspend in 1 ml PBS; centrifugation (400×g; 5 min; RT);wash cells twice with PBS. Add 100 μl Serin lysis buffer (ice cold) tothe cell pellet; resuspend the pellet and store on ice for 15 minutes.Remove debris by centrifugation at 15000×g for 10 min at 4° C. Transfer80-100 μl lysate supernatant in 96 well plate and store immediately at−80° C.

Neutrophil Elastase Activity Assay:

Frozen lysates were thawn at 37° C. for 10 minutes and stored on ice.Protein content was determined with Bradford protein assay. Lysates werediluted to 0.2-0.5 mg/ml protein in serine protease buffer+HSA.

Standard: NE (100 μg/ml stocksolution in Tris-buffer; stored at −80° C.)was diluted in Tris-buffer+HSA to 750 ng/ml, and further seriallydiluted 1:2 for the standard curve.

Buffer, blank, standard and lysate samples were transferred into 384well plate

Pipetting plan Blank: 5 μl Tris-buffer +10 μl Tris-buffer + HSA +5 μlSubstrate Standard: 5 μl Tris-buffer +10 μl NE (diff.conc.) +5 μlSubstrate Lysate: 5 μl Tris-buffer +10 μl Lysat +5 μl Substrate

The increase in fluorescence (Ex360 nm/Em 460 nm) is determined over 30minutes with a Molecular Device Spectramax M5 Fluorescence Reader.Kinetic Reduction (Vmax units/sec); 4 vmax points. The amount ofneutrophil elastase (ng/ml) is calculated using the standard curve andthe Spectramax software. The result is interpolated to ng/mg lysateprotein using excel formula functions. Percent inhibition in thecompound-treated lysate samples is calculated relative to theDMSO-treated control-sample (100−(compound-sample*100)/control-sample) Atest compound will give values between 0% and 100% inhibition ofneutrophil elastase. IC50 is calculated using Graphpad Prism; nonlinearfitting (log(inhibitor) vs. response—Variable slope). The IC50 value isinterpolated as the concentration of test compound which leads to aneutrophil elastase activity reduction of 50% (relative to theDMSO-treated control).

Reduction of NE-activity in U937 cells Example IC50 [μM] 1 0.134 2 0.2814 0.050 7 0.561 8 0.469 10 0.426 11 0.328 12 0.450Determination of Metabolic Stability with Human Liver Microsomes

The metabolic degradation of the test compound is assayed at 37° C. withpooled human liver microsomes. The final incubation volume of 100 μl pertime point contains TRIS buffer pH 7.6 (0.1 M), magnesium chloride (5mM), microsomal protein (1 mg/ml) and the test compound at a finalconcentration of 1 μM. Following a short preincubation period at 37° C.,the reactions are initiated by addition of beta-nicotinamide adeninedinucleotide phosphate, reduced form (NADPH, 1 mM) and terminated bytransfering an aliquot into acetonitrile after different time points.Additionally, the NADPH-independent degradation is monitored inincubations without NADPH, terminated at the last time point. The [%]remaining test compound after NADPH independent incubation is reflectedby the parameter c(control) (metabolic stability). The quenchedincubations are pelleted by centrifugation (10′000 g, 5 min). An aliquotof the supernatant is assayed by LC-MS/MS for the amount of parentcompound.

The half-life (t1/2 INVITRO) is determined by the slope of thesemilogarithmic plot of the concentration-time profile. The intrinsicclearance (CL_INTRINSIC) is calculated by considering the amount ofprotein in the incubation:CL_INTRINSIC[μl/min/mg protein]=(In 2/(half-life[min]*proteincontent[mg/ml]))*1′000.The half-life (t1/2 INVITRO) values of selected compounds in themetabolic stability assay described above are listed in the followingtable

In vitro stability in human liver microsome incubations Ex. t1/2 [min] 1120 2 120 4 88 7 >130 8 >130 9 >130 10 >130 11 >130 12 64

Combinations

The compounds of general formula I may be used on their own or combinedwith other active substances of formula I according to the invention.The compounds of general formula I may optionally also be combined withother pharmacologically active substances. These include,12-adrenoceptor-agonists (short and long-acting), anti-cholinergics(short and long-acting), anti-inflammatory steroids (oral and topicalcorticosteroids), cromoglycate, methylxanthine,dissociated-glucocorticoidmimetics, PDE3 inhibitors, PDE4-inhibitors,PDE7-inhibitors, LTD4 antagonists, EGFR-inhibitors, Dopamine agonists,PAF antagonists, Lipoxin A4 derivatives, FPRL1 modulators, LTB4-receptor(BLT1, BLT2) antagonists, Histamine H1 receptor antagonists, HistamineH4 receptor antagonists, dual Histamine H1/H3-receptor antagonists,PI3-kinase inhibitors, inhibitors of non-receptor tyrosine kinases asfor example LYN, LCK, SYK, ZAP-70, FYN, BTK or ITK, inhibitors of MAPkinases as for example p38, ERK1, ERK2, JNK1, JNK2, JNK3 or SAP,inhibitors of the NF-κB signalling pathway as for example IKK2 kinaseinhibitors, iNOS inhibitors, MRP4 inhibitors, leukotriene biosyntheseinhibitors as for example 5-Lipoxygenase (5-LO) inhibitors, cPLA2inhibitors, Leukotriene A4 Hydrolase inhibitors or FLAP inhibitors,Non-steroidal anti-inflammatory agents (NSAIDs), CRTH2 antagonists,DP1-receptor modulators, Thromboxane receptor antagonists, CCR3antagonists, CCR4 antagonists, CCR1 antagonists, CCR5 antagonists, CCR6antagonists, CCR7 antagonists, CCR8 antagonists, CCR9 antagonists, CCR30antagonists, CXCR³ antagonists, CXCR⁴ antagonists, CXCR² antagonists,CXCR¹ antagonists, CXCR5 antagonists, CXCR6 antagonists, CX3CR³antagonists, Neurokinin (NK1, NK2) antagonists, Sphingosine 1-Phosphatereceptor modulators, Sphingosine 1 phosphate lyase inhibitors, Adenosinereceptor modulators as for example A2a-agonists, modulators ofpurinergic rezeptors as for example P2X7 inhibitors, Histone Deacetylase(HDAC) activators, Bradykinin (BK1, BK2) antagonists, TACE inhibitors,PPAR gamma modulators, Rho-kinase inhibitors, interleukin 1-betaconverting enzyme (ICE) inhibitors, Toll-Like receptor (TLR) modulators,HMG-CoA reductase inhibitors, VLA-4 antagonists, ICAM-1 inhibitors, SHIPagonists, GABAa receptor antagonist, ENaC-inhibitors,Prostasin-inhibitors, Matriptase-inhibitors, Melanocortin receptor(MC1R, MC2R, MC3R, MC4R, MC5R) modulators, CGRP antagonists, Endothelinantagonists, TNFα antagonists, anti-TNF antibodies, anti-GM-CSFantibodies, anti-CD46 antibodies, anti-IL-1 antibodies, anti-IL-2antibodies, anti-IL-4 antibodies, anti-IL-5 antibodies, anti-IL-13antibodies, anti-IL-4/IL-13 antibodies, anti-TSLP antibodies, anti-OX40antibodies, mucoregulators, immunotherapeutic agents, compounds againstswelling of the airways, compounds against cough, VEGF inhibitors,NE-inhibitors, MMP9 inhibitors, MMP12 inhibitors, but also combinationsof two or three active substances.

Preferred are betamimetics, anticholinergics, corticosteroids,PDE4-inhibitors, LTD4-antagonists, EGFR-inhibitors, CRTH2 inhibitors,5-LO-inhibitors, Histamine receptor antagonists and SYK-inhibitors,NE-inhibitors, MMP9 inhibitors, MMP12 inhibitors, but also combinationsof two or three active substances, i.e.:

-   -   Betamimetics with corticosteroids, PDE4-inhibitors,        CRTH2-inhibitors or LTD4-antagonists,    -   Anticholinergics with betamimetics, corticosteroids,        PDE4-inhibitors, CRTH2-inhibitors or LTD4-antagonists,    -   Corticosteroids with PDE4-inhibitors, CRTH2-inhibitors or        LTD4-antagonists    -   PDE4-inhibitors with CRTH2-inhibitors or LTD4-antagonists    -   CRTH2-inhibitors with LTD4-antagonists.

Indications

The compounds of the invention and their pharmaceutically acceptablesalts have activity as pharmaceuticals, in particular as inhibitors ofdipeptidyl peptidase I activity, and thus may be used in the treatmentof:

1. respiratory tract: obstructive diseases of the airways including:asthma, including bronchial, allergic, intrinsic, extrinsic,exercise-induced, drug-induced (including aspirin and NSAID-induced) anddust-induced asthma, both intermittent and persistent and of allseverities, and other causes of airway hyper-responsiveness; chronicobstructive pulmonary disease (COPD); bronchitis, including infectiousand eosinophilic bronchitis; emphysema; alpha1-antitrypsin deficiency,bronchiectasis; cystic fibrosis; sarcoidosis; farmer's lung and relateddiseases; hypersensitivity pneumonitis; lung fibrosis, includingcryptogenic fibrosing alveolitis, idiopathic interstitial pneumonias,fibrosis complicating anti-neoplastic therapy and chronic infection,including tuberculosis and aspergillosis and other fungal infections;complications of lung transplantation; vasculitic and thromboticdisorders of the lung vasculature, polyangiitis (Wegener Granulomatosis)and pulmonary hypertension; antitussive activity including treatment ofchronic cough associated with inflammatory and secretory conditions ofthe airways, and iatrogenic cough; acute and chronic rhinitis includingrhinitis medicamentosa, and vasomotor rhinitis; perennial and seasonalallergic rhinitis including rhinitis nervosa (hay fever); nasalpolyposis; acute viral infection including the common cold, andinfection due to respiratory syncytial virus, influenza, coronavirus(including SARS) and adenovirus;2. skin: psoriasis, atopic dermatitis, contact dermatitis or othereczematous dermatoses, and delayed-type hypersensitivity reactions;phyto- and photodermatitis; seborrhoeic dermatitis, dermatitisherpetiformis, lichen planus, lichen sclerosus et atrophica, pyodermagangrenosum, skin sarcoid, discoid lupus erythematosus, pemphigus,pemphigoid, epidermolysis bullosa, urticaria, angioedema, vasculitides,toxic erythemas, cutaneous eosinophilias, alopecia greata, male-patternbaldness, Sweet's syndrome, Weber-Christian syndrome, erythemamultiforme; cellulitis, both infective and non-infective; panniculitis;cutaneous lymphomas, non-melanoma skin cancer and other dysplasticlesions; drug-induced disorders including fixed drug eruptions;3. eyes: blepharitis; conjunctivitis, including perennial and vernalallergic conjunctivitis; iritis; anterior and posterior uveitis;choroiditis; autoimmune, degenerative or inflammatory disordersaffecting the retina; ophthalmitis including sympathetic ophthalmitis;sarcoidosis; infections including viral, fungal, and bacterial;4. genitourinary: nephritis including interstitial andglomerulonephritis; nephrotic syndrome; cystitis including acute andchronic (interstitial) cystitis and Hunner's ulcer; acute and chronicurethritis, prostatitis, epididymitis, oophoritis and salpingitis;vulvo-vaginitis; Peyronie's disease; erectile dysfunction (both male andfemale);5. allograft rejection: acute and chronic following, for example,transplantation of kidney, heart, liver, lung, bone marrow, skin orcornea or following blood transfusion; or chronic graft versus hostdisease;6. other auto-immune and allergic disorders including rheumatoidarthritis, irritable bowel syndrome, systemic lupus erythematosus,multiple sclerosis, Hashimoto's thyroiditis, Graves' disease, Addison'sdisease, diabetes mellitus, idiopathic thrombocytopaenic purpura,eosinophilic fasciitis, hyper-IgE syndrome, antiphospholipid syndromeand Sazary syndrome;7. oncology: treatment of common cancers including prostate, breast,lung, ovarian, pancreatic, bowel and colon, stomach, skin and braintumors and malignancies affecting the bone marrow (including theleukaemias) and lymphoproliferative systems, such as Hodgkin's andnon-Hodgkin's lymphoma; including the prevention and treatment ofmetastatic disease and tumour recurrences, and paraneoplastic syndromes;and,8. infectious diseases: virus diseases such as genital warts, commonwarts, plantar warts, hepatitis B, hepatitis C, herpes simplex virus,molluscum contagiosum, variola, human immunodeficiency virus (HIV),human papilloma virus (HPV), cytomegalovirus (CMV), varicella zostervirus (VZV), rhinovirus, adenovirus, coronavirus, influenza,para-influenza; bacterial diseases such as tuberculosis andmycobacterium avium, leprosy; other infectious diseases, such as fungaldiseases, chlamydia, Candida, aspergillus, cryptococcal meningitis,Pneumocystis carnii, cryptosporidiosis, histoplasmosis, toxoplasmosis,trypanosome infection and leishmaniasis.9. pain: Recent literature data from Cathepsin C-deficient mice point toa modulatory role of Cathepsin C in pain sensation. Accordingly,inhibitors of Cathepsin C may also be useful in the clinical setting ofvarious form of chronic pain, e.g. inflammatory or neuropathic pain.

For treatment of the above-described diseases and conditions, atherapeutically effective dose will generally be in the range from about0.01 mg to about 100 mg/kg of body weight per dosage of a compound ofthe invention; preferably, from about 0.1 mg to about 20 mg/kg of bodyweight per dosage. For Example, for administration to a 70 kg person,the dosage range would be from about 0.7 mg to about 7000 mg per dosageof a compound of the invention, preferably from about 7.0 mg to about1400 mg per dosage. Some degree of routine dose optimization may berequired to determine an optimal dosing level and pattern. The activeingredient may be administered from 1 to 6 times a day.

The actual pharmaceutically effective amount or therapeutic dosage willof course depend on factors known by those skilled in the art such asage and weight of the patient, route of administration and severity ofdisease. In any case the active ingredient will be administered atdosages and in a manner which allows a pharmaceutically effective amountto be delivered based upon patient's unique condition.

What we claim:
 1. A compound of formula I

wherein R¹ is independently selected from among H, C₁₋₆-alkyl-, halogen,HO—, C₁₋₆-alkyl-O—, H₂N—, C₁₋₆-alkyl-HN—, (C₁₋₆-alkyl)₂N— andC₁₋₆-alkyl-C(O)HN—; or two R¹ are together C₁₋₄-alkylene; R² is selectedfrom among R^(2.1); aryl-; optionally substituted with one, two or threeresidues independently selected from R^(2.1); optionally substitutedwith one R^(2.3); C₅₋₁₀-heteroaryl-; containing one, two, three or fourheteroatoms independently selected from among S, S(O), S(O)₂, O and N,wherein carbon atoms of the ring are optionally and independently fromeach other substituted with one, two or three R^(2.1); wherein nitrogenatoms of the ring are optionally and independently from each othersubstituted with one, two or three R^(2.2); wherein a carbon atom of thering is optionally substituted with one R^(2.3); a nitrogen atom of thering is optionally substituted with one R^(2.4); andC₅₋₁₀-heterocyclyl-; containing one, two, three or four heteroatomsindependently selected from among S, S(O), S(O)₂, O and N, wherein thering is fully or partially saturated, wherein carbon atoms of the ringare optionally and independently from each other substituted with one,two or three or four R^(2.1); wherein nitrogen atoms of the ring areoptionally and independently from each other substituted with one, twoor three R^(2.2); wherein a carbon atom of the ring is optionallysubstituted with one R^(2.3) or one R^(2.5); a nitrogen atom of the ringis optionally substituted with one R^(2.4) or R² and R⁴ are togetherwith two adjacent carbon atoms of the phenyl ring a 5- or 6-memberedaryl or heteroaryl, containing one, two or three heteroatomsindependently selected from among S, S(O), S(O)₂, O and N, whereincarbon atoms of the ring are optionally and independently from eachother substituted with one, two or three R^(2.1); wherein nitrogen atomsof the ring are optionally and independently from each other substitutedwith one, two or three R^(2.2); R^(2.1) is independently selected fromamong H, halogen, NC—, O═, HO—, H-A-, H-A-C₁₋₆-alkylene-, R^(2.1.1)-A-,C₁₋₆-alkyl-A-, C₃₋₈-cycloalkyl-A-, C₁₋₆-haloalkyl-A-,R^(2.1.1)—C₁₋₆-alkylene-A-, C₁₋₆-alkyl-A-C₁₋₆-alkylene-,C₃₋₈-cycloalkyl-A-C₁₋₆-alkylene-, C₁₋₆-haloalkyl-A-C₁₋₆-alkylene-,R^(2.1.1)—C₁₋₆-alkylene-A-C₁₋₆-alkylene-, R^(2.1.1)-A-C₁₋₆-alkylene-,HO—C₁₋₆-alkylene-A-, HO—C₁₋₆-alkylene-A-C₁₋₆-alkylene-,C₁₋₆-alkyl-O—C₁₋₆-alkylene-A— andC₁₋₆-alkyl-O—C₁₋₆-alkylene-A-C₁₋₆-alkylene- R^(2.1.1) is independentlyselected from among aryl-; optionally substituted independently fromeach other with one, two or three R^(2.1.1.1); C₅₋₁₀-heteroaryl-;containing one, two, three or four heteroatoms independently selectedfrom among S, S(O), S(O)₂, O and N, wherein carbon atoms of the ring areoptionally and independently from each other substituted with one, twoor three R^(2.1.1.1); wherein nitrogen atoms of the ring are optionallyand independently from each other substituted with one, two or threeR^(2.1.1.2); and C₅₋₁₀-heterocyclyl-; containing one, two, three or fourheteroatoms independently selected from among S, S(O), S(O)₂, O and N,wherein the ring is fully or partially saturated, wherein carbon atomsof the ring are optionally and independently from each other substitutedwith one, two or three or four R^(2.1.1.1); wherein nitrogen atoms ofthe ring are optionally and independently from each other substitutedwith one, two or three R^(2.1.1.2); R^(2.1.1.1) is independentlyselected from among halogen, HO—, O═, C₁₋₆-alkyl-, C₁₋₆-alkyl-O—,C₁₋₆-haloalkyl-, C₁₋₆-haloalkyl-O— and C₃₋₈-cycloalkyl-; R^(2.1.1.2) isindependently selected from among O═, C₁₋₆-alkyl-, C₁₋₆-haloalkyl-;C₃₋₈-cycloalkyl-, C₁₋₆-alkyl-O—C₁₋₆-alkyl-, H(O)C—, C₁₋₆-alkyl-(O)C—,tetrahydrofuranylmethyl- and tetrahydropyranylmethyl-; R^(2.2) isindependently selected from among H-A-C₁₋₆-alkylene-, C₃₋₈-cycloalkyl-,C₁₋₆-alkyl-A-C₁₋₆-alkylene-, C₃₋₈-cycloalkyl-A-C₁₋₆-alkylene-,C₁₋₆-haloalkyl-A-C₁₋₆-alkylene-, R^(2.1.1)-A-C₁₋₆-alkylene-,C₁₋₆-alkyl-S(O)₂—, C₁₋₆-alkyl-C(O)— and R^(2.1.1)-A-; R^(2.3) and R⁴ aretogether selected from among —O—, —S—, —N(R^(2.3.1))—,—C(O)N(R^(2.3.1))—, —N(R^(2.3.1))C(O)—, —S(O)₂N(R^(2.3.1))—,—N(R^(2.3.1))S(O)₂—, —C(O)O—, —OC(O)—, —C(O)—, —S(O)—, —S(O)₂—, R^(2.3),R^(2.3), —C(R^(2.3.2))═C(R^(2.3.2))—, —C═N—, —N═C—, —C(R^(2.3.2))₂—O—,—O—C(R^(2.3.2))₂—, —C(R^(2.3.2))₂N(R^(2.3.1))—,—N(R^(2.3.1))C(R^(2.3.2))₂— and —C₁₋₄-alkylene-; R^(2.3.1) isindependently selected from among H, C₁₋₆-alkyl-, C₁₋₆-haloalkyl-;C₃₋₈-cycloalkyl-, HO—C₁₋₄-alkylene-, (C₁₋₄-alkyl)-O—C₁₋₄-alkylene-,H₂N—C₁₋₄-alkylene-, (C₁₋₄-alkyl)HN—C₁₋₄-alkylene- and(C₁₋₄-alkyl)₂N—C₁₋₄-alkylene-; R^(2.3.2) is independently selected fromamong H, C₁₋₆-alkyl-, C₁₋₆-haloalkyl-; C₃₋₈-cycloalkyl-,HO—C₁₋₄-alkylene-, (C₁₋₄-alkyl)-O—C₁₋₄-alkylene-, H₂N—C₁₋₄-alkylene-,(C₁₋₄-alkyl)HN—C₁₋₄-alkylene- and (C₁₋₄-alkyl)₂N—C₁₋₄-alkylene-; R^(2.4)and R⁴ are together selected from among —N(R^(2.4.1))—,—C(O)N(R^(2.4.1))—, —N(R^(2.4.1))C(O)—, —S(O)₂N(R^(2.4.1))—,—N(R^(2.4.1))S(O)₂—, —C(O)—, —S(O)—, —S(O)₂—,—C(R^(2.4.2))═C(R^(2.4.2))—, —C═N—, —N═C—, —C(R^(2.4.2))₂N(R^(2.4.1))—and —N(R^(2.4.1))C(R^(2.4.2))₂—, —C₁₋₄-alkylene-; and R^(2.4.1) isindependently selected from among H, C₁₋₆-alkyl-, C₁₋₆-haloalkyl-;C₃₋₈-cycloalkyl-, HO—C₁₋₄-alkylene-, (C₁₋₄-alkyl)-O—C₁₋₄-alkylene-,H₂N—C₁₋₄-alkylene-, (C₁₋₄-alkyl)HN—C₁₋₄-alkylene- and(C₁₋₄-alkyl)₂N—C₁₋₄-alkylene-; R^(2.4.2) is independently selected fromamong H, C₁₋₆-alkyl-, C₁₋₆-haloalkyl-; C₃₋₈-cycloalkyl-,HO—C₁₋₄-alkylene-, (C₁₋₄-alkyl)-O—C₁₋₄-alkylene-, H₂N—C₁₋₄-alkylene-,(C₁₋₄-alkyl)HN—C₁₋₄-alkylene- and (C₁₋₄-alkyl)₂N—C₁₋₄-alkylene-; R^(2.5)and R⁴ are together selected from among —C(R^(2.5.1))=, ═C(R^(2.5.1))—and —N═; and R^(2.5.1) is independently selected from among H,C₁₋₆-alkyl-, C₁₋₆-haloalkyl-; C₃₋₈-cycloalkyl-, HO—C₁₋₄-alkylene-,(C₁₋₄-alkyl)-O—C₁₋₄-alkylene-, H₂N—C₁₋₄-alkylene-,(C₁₋₄-alkyl)HN—C₁₋₄-alkylene- and (C₁₋₄-alkyl)₂N—C₁₋₄-alkylene-; R³ is Hor F; R⁴ is independently selected from among H, F, Cl, phenyl-H₂C—O—,HO—, C₁₋₆-alkyl-, C₁₋₆-haloalkyl-, C₃₋₈-cycloalkyl-, C₁₋₆-alkyl-O—,C₁₋₆-haloalkyl-O—, C₁₋₆-alkyl-HN—, (C₁₋₆-alkyl)₂-HN—,C₁₋₆-alkyl-HN—C₁₋₄-alkylene- and (C₁₋₆-alkyl)₂-HN—C₁₋₄-alkylene-; A is abond or independently selected from among —O—, —S—, —N(R⁵)—,—C(O)N(R⁵)—, —N(R⁵)C(O)—, —S(O)₂N(R⁵)—, —N(R⁵)S(O)₂—,—S(O)(═NR⁵)—N(R⁵)—, —N(R⁵)(NR⁵═) S(O)—, —S(═NR⁵)₂—N(R⁵)—,—N(R⁵)(NR⁵═)₂S—, —C(R⁵)═C(R⁵)—, —C≡C—, —C(O)O—, —OC(O)—, —C(O)—, —S(O)—,—S(O)₂—, —S(═NR⁵)—, —S(O)(═NR⁵)—, —S(═NR⁵)₂—, —(R⁵)(O)S═N—, —(R⁵N═)(O)S—and —N═(O)(R⁵)S—; R⁵ is independently selected from among H, C₁₋₆-alkyl-and NC—; or a salt thereof.
 2. The compound of formula 1, according toclaim 1, wherein R¹ is R^(1.a) and R^(1.a) is independently selectedfrom among H, C₁₋₄-alkyl-, F— and HO—.
 3. The compound of formula 1,according to claim 1, wherein R⁴ is R^(4.a) and R^(4.a) is H, F, Cl,phenyl-H₂C—O—, HO—, C₁₋₄-alkyl-, C₁₋₄-haloalkyl-, C₃₋₆-cycloalkyl-,C₁₋₄-alkyl-O— and C₁₋₄-haloalkyl-O—.
 4. The compound of formula 1,according to claim 1, wherein R⁴ is R^(4.b) and R^(4.b) is H or F. 5.The compound of formula 1, according to claim 1, wherein A is A^(a) andA^(a) is a bond or independently selected from among —O—, —C(O)N(R⁵)—,—N(R⁵)C(O)—, —S(O)₂N(R⁵)—, —N(R⁵)S(O)₂—, —C(O)O—, —OC(O)—, —C(O)—,—S(O)₂—, —(R⁵)(O)S═N—, —(R^(S)N═)(O)S— and —N═(O)(R⁵)S—, and R⁵ isR^(5.a) and R^(5.a) is independently selected from among H, C₁₋₄-alkyl-and NC—.
 6. The compound of formula 1, according to claim 1, wherein R²is R^(2.1) and R^(2.1) is R^(2.1.a) and R^(2.1.a) is selected from amongH, halogen, NC—, O═, HO—, H-A-, H-A-C₁₋₄-alkylene-, R^(2.1.1)-A-,C₁₋₄-alkyl-A-, C₃₋₆-cycloalkyl-A-, C₁₋₄-haloalkyl-A-,R^(2.1.1)—C₁₋₄-alkylene-A-, C₁₋₄-alkyl-A-C₁₋₄-alkylene-,C₃₋₆-cycloalkyl-A-C₁₋₄-alkylene-, C₁₋₄-haloalkyl-A-C₁₋₄-alkylene-,R^(2.1.1)—C₁₋₄-alkylene-A-C₁₋₄-alkylene-, R^(2.1.1)-A-C₁₋₄-alkylene-,HO—C₁₋₄-alkylene-A-, HO—C₁₋₄-alkylene-A-C₁₋₄-alkylene-,C₁₋₄-alkyl-O—C₁₋₄-alkylene-A- andC₁₋₄-alkyl-O—C₁₋₄-alkylene-A-C₁₋₄-alkylene-; and R^(2.1.1) isR^(2.1.1.a) and R^(2.1.1.a) is selected from among aryl-, optionallysubstituted independently from each other with one, two or threeresidues independently selected from R^(2.1.1.1); C₅₋₁₀-heteroaryl-,containing one, two, three or four heteroatoms selected independentlyfrom S, S(O), S(O)₂, O and N, wherein carbon atoms of the ring areoptionally and independently from each other substituted with one, twoor three R^(2.1.1.1); wherein nitrogen atoms of the ring are optionallyand independently from each other substituted with one, two or threeR^(2.1.1.2); and C₅₋₁₀-heterocyclyl-, containing one, two, three or fourheteroatoms selected independently from S, S(O), S(O)₂, O and N and thering is fully or partially saturated, wherein carbon atoms of the ringare optionally and independently from each other substituted with one,two or three R^(2.1.1.1); wherein nitrogen atoms of the ring areoptionally and independently from each other substituted with one, twoor three R^(2.1.1.2); and R^(2.1.1.1) is independently selected fromamong halogen, HO—, O═, C₁₋₄-alkyl-, C₁₋₄-alkyl-O—, C₁₋₄-haloalkyl-,C₁₋₄-haloalkyl-O— and C₃₋₆-cycloalkyl-; and R^(2.1.1.2) is independentlyselected from among O═, C₁₋₄-alkyl-, C₁₋₄-haloalkyl-; C₃₋₆-cycloalkyl-,C₁₋₄-alkyl-O—C₁₋₄-alkyl-, H(O)C—, C₁₋₄-alkyl-(O)C—,tetrahydrofuranylmethyl- and tetrahydropyranylmethyl.
 7. The compound offormula 1, according to claim 1, wherein R² is R^(2.d) and R^(2.d) isphenyl; optionally substituted with one, two or three residuesindependently selected from R^(2.1) and R^(2.1) is R^(2.1.a) andR^(2.1.a) is selected from among H, halogen, NC—, O═, HO—, H-A-,H-A-C₁₋₄-alkylene-, R^(2.1.1)-A-, C₁₋₄-alkyl-A-, C₃₋₆-cycloalkyl-A-,C₁₋₄-haloalkyl-A-, R^(2.1.1)—C₁₋₄-alkylene-A-,C₁₋₄-alkyl-A-C₁₋₄-alkylene-, C₃₋₆-cycloalkyl-A-C₁₋₄-alkylene-,C₁₋₄-haloalkyl-A-C₁₋₄-alkylene-,R^(2.1.1)—C₁₋₄-alkylene-A-C₁₋₄-alkylene-, R^(2.1.1)-A-C₁₋₄-alkylene-,HO—C₁₋₄-alkylene-A-, HO—C₁₋₄-alkylene-A-C₁₋₄-alkylene-,C₁₋₄-alkyl-O—C₁₋₄-alkylene-A— andC₁₋₄-alkyl-O—C₁₋₄-alkylene-A-C₁₋₄-alkylene-; and R^(2.1.1) isR^(2.1.l.a) and R^(2.1.1.a) is selected from among aryl-, optionallysubstituted independently from each other with one, two or threeresidues independently selected from R^(2.1.1.1); C₅₋₁₀-heteroaryl-,containing one, two, three or four heteroatoms selected independentlyfrom S, S(O), S(O)₂, O and N, wherein carbon atoms of the ring areoptionally and independently from each other substituted with one, twoor three R^(2.1.1.1); wherein nitrogen atoms of the ring are optionallyand independently from each other substituted with one, two or threeR^(2.1.1.2); and C₅₋₁₀-heterocyclyl-, containing one, two, three or fourheteroatoms selected independently from S, S(O), S(O)₂, O and N and thering is fully or partially saturated, wherein carbon atoms of the ringare optionally and independently from each other substituted with one,two or three R^(2.1.1.1); wherein nitrogen atoms of the ring areoptionally and independently from each other substituted with one, twoor three R^(2.1.1.2); and R^(2.1.1.1) is independently selected fromamong halogen, HO—, O═, C₁₋₄-alkyl-, C₁₋₄-alkyl-O—, C₁₋₄-haloalkyl- andC₁₋₄-haloalkyl-O—, C₃₋₆-cycloalkyl-; and R^(2.1.1.2) is independentlyselected from among O═, C₁₋₄-alkyl-, C₁₋₄-haloalkyl-; C₃₋₆-cycloalkyl-,C₁₋₄-alkyl-O—C₁₋₄-alkyl-, H(O)C—, C₁₋₄-alkyl-(O)C—,tetrahydrofuranylmethyl- and tetrahydropyranylmethyl.
 8. The compound offormula 1, according to claim 1, wherein R² is R^(2.g) and R^(2.g) isselected from among

wherein carbon atoms of the ring are optionally and independently fromeach other substituted with one, two or three R^(2.1); wherein possiblyavailable nitrogen atoms of the ring are optionally and independentlyfrom each other substituted with R^(2.2); and R^(2.1) is R^(2.1.a) andR^(2.1.a) is selected from among H, halogen, NC—, O═, HO—, H-A-,H-A-C₁₋₄-alkylene-, R^(2.1.1)-A-, C₁₋₄-alkyl-A-, C₃₋₆-cycloalkyl-A-,C₁₋₄-haloalkyl-A-, R^(2.1.1)—C₁₋₄-alkylene-A-,C₁₋₄-alkyl-A-C₁₋₄-alkylene-, C₃₋₆-cycloalkyl-A-C₁₋₄-alkylene-,C₁₋₄-haloalkyl-A-C₁₋₄-alkylene-,R^(2.1.1)—C₁₋₄-alkylene-A-C₁₋₄-alkylene-, R^(2.1.1)-A-C₁₋₄-alkylene-,HO—C₁₋₄-alkylene-A-, HO—C₁₋₄-alkylene-A-C₁₋₄-alkylene-,C₁₋₄-alkyl-O—C₁₋₄-alkylene-A— andC₁₋₄-alkyl-O—C₁₋₄-alkylene-A-C₁₋₄-alkylene-; and R^(2.1.1) isR^(2.1.1.a) and R^(2.1.1.a) is selected from among aryl-, optionallysubstituted independently from each other with one, two or threeresidues independently selected from R^(2.1.1.1); C₅₋₁₀-heteroaryl-,containing one, two, three or four heteroatoms selected independentlyfrom S, S(O), S(O)₂, O and N, wherein carbon atoms of the ring areoptionally and independently from each other substituted with one, twoor three R^(2.1.1.1); wherein nitrogen atoms of the ring are optionallyand independently from each other substituted with one, two or threeR^(2.1.1.2); and C₅₋₁₀-heterocyclyl-, containing one, two, three or fourheteroatoms selected independently from S, S(O), S(O)₂, O and N and thering is fully or partially saturated, wherein carbon atoms of the ringare optionally and independently from each other substituted with one,two or three R^(2.1.1.1); wherein nitrogen atoms of the ring areoptionally and independently from each other substituted with one, twoor three R^(2.1.1.2); and R^(2.1.1.1) is independently selected fromamong halogen, HO—, O═, C₁₋₄-alkyl-, C₁₋₄-alkyl-O—, C₁₋₄-haloalkyl-,C₁₋₄-haloalkyl-O— and C₃₋₆-cycloalkyl-; and R^(2.1.1.2) is independentlyselected from among O═, C₁₋₄-alkyl-, C₁₋₄-haloalkyl-; C₃₋₆-cycloalkyl-,C₁₋₄-alkyl-O—C₁₋₄-alkyl-, H(O)C—, C₁₋₄-alkyl-(O)C—,tetrahydrofuranylmethyl- and tetrahydropyranylmethyl; and R^(2.2) isR^(2.2.a) and R^(2.2.a) is independently selected from amongH-A-C₁₋₄-alkylene-, C₃₋₆-cycloalkyl-, C₁₋₄-alkyl-A-C₁₋₄-alkylene-,C₃₋₆-cycloalkyl-A-C₁₋₄-alkylene-, C₁₋₄-haloalkyl-A-C₁₋₄-alkylene-,R^(2.1.1)-A-C₁₋₄-alkylene-, C₁₋₄-alkyl-S(O)₂—, C₁₋₄-alkyl-C(O)— andR^(2.1.1)-A-.
 9. The compound of formula 1, according to claim 1,wherein R² is R^(2.j) and R^(2.j) is selected from among

wherein carbon atoms of the ring are optionally and independently fromeach other substituted with one, two or three R^(2.1); wherein possiblyavailable nitrogen atoms of the ring are optionally and independentlyfrom each other substituted with R^(2.2); and R^(2.1) is R^(2.1.a) andR^(2.1.a) is selected from among H, halogen, NC—, O═, HO—, H-A-,H-A-C₁₋₄-alkylene-, R^(2.1.1)-A-, C₁₋₄-alkyl-A-, C₃₋₆-cycloalkyl-A-,C₁₋₄-haloalkyl-A-, R^(2.1.1)—C₁₋₄-alkylene-A-,C₁₋₄-alkyl-A-C₁₋₄-alkylene-, C₃₋₆-cycloalkyl-A-C₁₋₄-alkylene-,C₁₋₄-haloalkyl-A-C₁₋₄-alkylene-,R^(2.1.1)—C₁₋₄-alkylene-A-C₁₋₄-alkylene-, R^(2.1.1)-A-C₁₋₄-alkylene-,HO—C₁₋₄-alkylene-A-, HO—C₁₋₄-alkylene-A-C₁₋₄-alkylene-,C₁₋₄-alkyl-O—C₁₋₄-alkylene-A— andC₁₋₄-alkyl-O—C₁₋₄-alkylene-A-C₁₋₄-alkylene-; and R^(2.1.1) isR^(2.1.1.a) and R^(2.1.1.a) is selected from among aryl-, optionallysubstituted independently from each other with one, two or threeresidues independently selected from R^(2.1.1.1); C₅₋₁₀-heteroaryl-,containing one, two, three or four heteroatoms selected independentlyfrom S, S(O), S(O)₂, O and N, wherein carbon atoms of the ring areoptionally and independently from each other substituted with one, twoor three R^(2.1.1.1); wherein nitrogen atoms of the ring are optionallyand independently from each other substituted with one, two or threeR^(2.1.1.2); and C₅₋₁₀-heterocyclyl-, containing one, two, three or fourheteroatoms selected independently from S, S(O), S(O)₂, O and N and thering is fully or partially saturated, wherein carbon atoms of the ringare optionally and independently from each other substituted with one,two or three R^(2.1.1.1); wherein nitrogen atoms of the ring areoptionally and independently from each other substituted with one, twoor three R^(2.1.1.2); and R^(2.1.1.1) is independently selected fromamong halogen, HO—, O═, C₁₋₄-alkyl-, C₁₋₄-alkyl-O—, C₁₋₄-haloalkyl-,C₁₋₄-haloalkyl-O— and C₃₋₆-cycloalkyl-; and R^(2.1.1.2) is independentlyselected from among O═, C₁₋₄-alkyl-, C₁₋₄-haloalkyl-; C₃₋₆-cycloalkyl-,C₁₋₄-alkyl-O—C₁₋₄-alkyl-, H(O)C—, C₁₋₄-alkyl-(O)C—,tetrahydrofuranylmethyl- and tetrahydropyranylmethyl; and R^(2.2) isR^(2.2.a) and R^(2.2.a) is independently selected from amongH-A-C₁₋₄-alkylene-, C₃₋₆-cycloalkyl-, C₁₋₄-alkyl-A-C₁₋₄-alkylene-,C₃₋₆-cycloalkyl-A-C₁₋₄-alkylene-, C₁₋₄-haloalkyl-A-C₁₋₄-alkylene-,R^(2.1.1)-A-C₁₋₄-alkylene-, C₁₋₄-alkyl-S(O)₂—, C₁₋₄-alkyl-C(O)— andR^(2.1.1)-A-.
 10. The compound of formula 1, according to claim 1,wherein R² is R^(2.m) and R^(2.m) is together with R⁴ and two adjacentcarbon atoms of the phenyl ring a 5- or 6-membered aryl or heteroaryl,containing one, two or three heteroatoms independently selected fromamong S, S(O), S(O)₂, O and N, wherein carbon atoms of the ring areoptionally and independently from each other substituted with one, twoor three R^(2.1), wherein possibly available nitrogen atoms of the ringare optionally and independently from each other substituted with one,two or three R^(2.2); and R^(2.1) is R^(2.1.a) and R^(2.1.a) is selectedfrom among H, halogen, NC—, O═, HO—, H-A-, H-A-C₁₋₄-alkylene-,R^(2.1.1)-A-, C₁₋₄-alkyl-A-, C₃₋₆-cycloalkyl-A-, C₁₋₄-haloalkyl-A-,R^(2.1.1)—C₁₋₄-alkylene-A-, C₁₋₄-alkyl-A-C₁₋₄-alkylene-,C₃₋₆-cycloalkyl-A-C₁₋₄-alkylene-, C₁₋₄-haloalkyl-A-C₁₋₄-alkylene-,R^(2.1.1)—C₁₋₄-alkylene-A-C₁₋₄-alkylene-, R^(2.1.1)-A-C₁₋₄-alkylene-,HO—C₁₋₄-alkylene-A-, HO—C₁₋₄-alkylene-A-C₁₋₄-alkylene-,C₁₋₄-alkyl-O—C₁₋₄-alkylene-A— andC₁₋₄-alkyl-O—C₁₋₄-alkylene-A-C₁₋₄-alkylene-; and R^(2.1.1) isR^(2.1.1.a) and R^(2.1.1.a) is selected from among aryl-, optionallysubstituted independently from each other with one, two or threeresidues independently selected from R^(2.1.1.1); C₅₋₁₀-heteroaryl-,containing one, two, three or four heteroatoms selected independentlyfrom S, S(O), S(O)₂, O and N, wherein carbon atoms of the ring areoptionally and independently from each other substituted with one, twoor three R^(2.1.1.1); wherein nitrogen atoms of the ring are optionallyand independently from each other substituted with one, two or threeR^(2.1.1.2); C₅₋₁₀-heterocyclyl-, containing one, two, three or fourheteroatoms selected independently from S, S(O), S(O)₂, O and N and thering is fully or partially saturated, wherein carbon atoms of the ringare optionally and independently from each other substituted with one,two or three R^(2.1.1.1); wherein nitrogen atoms of the ring areoptionally and independently from each other substituted with one, twoor three R^(2.1.1.2); and R^(2.1.1.1) is independently selected fromamong halogen, HO—, O═, C₁₋₄-alkyl-, C₁₋₄-alkyl-O—, C₁₋₄-haloalkyl-,C₁₋₄-haloalkyl-O— and C₃₋₆-cycloalkyl-; and R^(2.1.1.2) is independentlyselected from among O═, C₁₋₄-alkyl-, C₁₋₄-haloalkyl-; C₃₋₆-cycloalkyl-,C₁₋₄-alkyl-O—C₁₋₄-alkyl-, H(O)C—, C₁₋₄-alkyl-(O)C—,tetrahydrofuranylmethyl- and tetrahydropyranylmethyl; and R^(2.2) isR^(2.2.a) and R^(2.2.a) is independently selected from amongH-A-C₁₋₄-alkylene-, C₃₋₆-cycloalkyl-, C₁₋₄-alkyl-A-C₁₋₄-alkylene-,C₃₋₆-cycloalkyl-A-C₁₋₄-alkylene-, C₁₋₄-haloalkyl-A-C₁₋₄-alkylene-,R^(2.1.1)-A-C₁₋₄-alkylene-, C₁₋₄-alkyl-S(O)₂—, C₁₋₄-alkyl-C(O)— andR^(2.1.1)-A-.
 11. The compound of formula 1, according to claim 1,wherein R² is R^(2.t) and R^(2.t) is selected from among thesubstituents (a2) to (g2)

wherein carbon atoms of the rings are optionally and independently fromeach other substituted with one, two or three R^(2.1); wherein anitrogen atom of the ring is optionally substituted with R^(2.2), or asalt thereof.
 12. The compound of formula 1 according to claim 1,wherein R¹ is R^(1.b) and R^(1.b) is H; R² is selected from amongR^(2.1); phenyl-; optionally substituted with one or two residuesindependently selected from R^(2.1); optionally substituted with oneR^(2.3); C₅-heteroaryl-; containing two or three independently selectedfrom among S, O and N, wherein carbon atoms of the ring are optionallyand independently from each other substituted with one R^(2.1); whereinnitrogen atoms of the ring are optionally and independently from eachother substituted with one R^(2.2); monocyclic C₆-heterocyclylcontaining one or two nitrogen atoms, wherein the ring is fully orpartially saturated, wherein carbon atoms of the ring are optionally andindependently from each other substituted with one R^(2.1); whereinnitrogen atoms of the ring are optionally and independently from eachother substituted with one R^(2.2); bicyclic C₉₋₁₀-heterocyclyl-;containing one, two, three or four heteroatoms independently selectedfrom among S(O)₂, O and N, wherein the ring is fully or partiallysaturated, wherein carbon atoms of the ring are optionally andindependently from each other substituted with one, two or threeR^(2.1); wherein nitrogen atoms of the ring are optionally andindependently from each other substituted with one R^(2.2); R^(2.1) isindependently selected from among halogen, NC—, O═, H-A-,H-A-C₁₋₄-alkylene-, R^(2.1.1)-A-, C₁₋₄-alkyl-A-, C₃₋₆-cycloalkyl-A-,R^(2.1.1)—C₁₋₄-alkylene-A-, C₁₋₄-alkyl-A-C₁₋₄-alkylene- andHO—C₁₋₄-alkylene-A-C₁₋₄-alkylene-; R^(2.1.1) is independently selectedfrom among phenyl-; and C_(5 or 6)-heterocyclyl-; containing one or twoheteroatoms independently selected from among O and N, wherein the ringis fully or partially saturated, wherein nitrogen atoms of the ring areoptionally and independently from each other substituted with oneC₁₋₄-alkyl-; R^(2.2) is independently selected from amongH-A-C₁₋₄-alkylene-, C₃₋₆-cycloalkyl-, C₁₋₄-alkyl-A-C₁₋₄-alkylene-,R^(2.1.1)-A-C₁₋₄-alkylene- and C₁₋₄-alkyl-C(O)—; R^(2.3) and R⁴ aretogether a group selected from among —N(R^(2.3.1))—, —C(O)N(R^(2.3.2))—and —N(R^(2.3.1))C(O)—; R^(2.3.1) is independently selected from amongH— and H₃C—; R³ is H, F; R⁴ is R^(4.b) and R^(4.b) is H or F; A is abond or independently selected from among —O—, —C(O)N(R⁵)—, —N(R⁵)C(O)—,—S(O)₂N(R⁵)—, —N(R⁵)S(O)₂—, —C(O)O—, —OC(O)—, —C(O)—, —S(O)₂— and—N═(O)(R⁵)S—; R⁵ is independently selected from among H— andC₁₋₄-alkyl-; or a salt thereof.
 13. A compound of formula 1′

wherein R¹, R², R³ and R⁴ have the meaning of claim
 1. 14. Apharmaceutical composition, comprising a compound of formula 1 accordingto claim 1 or a pharmaceutically acceptable salt thereof.
 15. Thepharmaceutical composition according to claim 14 further comprising apharmaceutically active compound selected from the group consisting ofbetamimetics, anticholinergics, corticosteroids, PDE4-inhibitors,LTD4-antagonists, EGFR-inhibitors, CRTH2 inhibitors, 5-LO-inhibitors,Histamine receptor antagonists, CCR9 antagonists and SYK-inhibitors,NE-inhibitors, MMP9 inhibitors and MMP12 inhibitors, or combinations oftwo or three of the pharmaceutically active compound.